Immunotherapy has been one of the hot topics in the field of colorectal cancer research in recent years. Patients with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) are the main beneficiaries of immunotherapy. The response rate of patients with dMMR/MSI-H colorectal cancer receiving neoadjuvant immunotherapy is nearly 100%, of which the pathological complete response rate approximately accounts for 60%-67%. The prospect of neoadjuvant immunotherapy in dMMR or MSI-H colorectal cancer patients, especially in the rectal cancer patients, lies in achieving sustainable clinical complete response so as to achieve organ preservation and avoid adverse effects on reproductive, sexual, bowel and bladder function after surgery and radiotherapy. Studies have shown that part of the colorectal cancer patients of microsatellite stability (MSS) or mismatch repair proficient (pMMR) can respond to neoadjuvant immunotherapy in combination with other treatment methods such as radiotherapy and chemotherapy. In pMMR or MSS colorectal cancer, optimizing neoadjuvant immunotherapy regimens and finding effective efficacy prediction biomarkers are important research directions. In neoadjuvant immunotherapy, overcoming primary and secondary resistance and identifying the pseudoprogression and hyperprogression of neoadjuvant immunotherapy are clinical challenges that require attention. This paper comprehensively reviews the research progress, controversies,challenges and future research directions of neoadjuvant immunotherapy (mainly immune checkpoint inhibitors) in colorectal cancer.
Humans ; Neoadjuvant Therapy/methods* ; Colorectal Neoplasms/drug therapy* ; Colonic Neoplasms/pathology* ; Immunotherapy/methods* ; DNA Mismatch Repair ; Microsatellite Instability

Objective: To investigate the safety and efficacy of laparoscopic surgery in locally advanced gastric cancer patients with neoadjuvant SOX chemotherapy combined with PD-1 inhibitor immunotherapy. Methods: Between November 2020 and April 2021, patients with locally advanced gastric cancer who were admitted to the Union Hospital of Tongji Medical College of Huazhong University of Science and Technology were prospectively enrolled in this study. Inclusion criteria were: (1) patients who signed the informed consent form voluntarily before participating in the study; (2) age ranging from 18 to 75 years; (3) patients staged preoperatively as cT3-4N+M0 by the TNM staging system; (4) Eastern Collaborative Oncology Group score of 0-1; (5) estimated survival of more than 6 months, with the possibility of performing R0 resection for curative purposes; (6) sufficient organ and bone marrow function within 7 days before enrollment; and (7) complete gastric D2 radical surgery. Exclusion criteria were: (1) history of anti-PD-1 or PD-L1 antibody therapy and chemotherapy; (2) treatment with corticosteroids or other immunosuppre- ssants within 14 days before enrollment; (3) active period of autoimmune disease or interstitial pneumonia; (4) history of other malignant tumors; (5) surgery performed within 28 days before enrollment; and (6) allergy to the drug ingredients of the study. Follow-up was conducted by outpatient and telephone methods. During preoperative SOX chemotherapy combined with PD-1 inhibitor immunotherapy, follow-up was conducted every 3 weeks to understand the occurrence of adverse reactions of the patients; follow-up was conducted once after 1 month of surgical treatment to understand the adverse reactions and survival of patients. Observation indicators were: (1) condition of enrolled patients; (2) reassessment after preoperative therapy and operation received (3) postoperative conditions and pathological results. Evaluation criteria were: (1) tumor staged according to the 8th edition of the American Joint Committee on Cancer (AJCC) TNM staging system; (2) tumor regression grading (TRG) of pathological results were evaluated with reference to AJCC standards; (3) treatment-related adverse reactions were evaluated according to version 5.0 of the Common Terminology Criteria for Adverse Events; (4) tumor response was evaluated by CT before and after treatment with RECIST V1.1 criteria; and (5) Clavien-Dindo complication grading system was used for postoperative complications assessment. Results: A total of 30 eligible patients were included. There were 25 males and 5 females with a median age of 60.5 (35-74) years. The primary tumor was located in the gastroesophageal junction in 12 cases, in the upper stomach in 8, in the middle stomach in 7, and in the lower stomach in 3. The preoperative clinical stage of 30 cases was III. Twenty-one patients experienced adverse reactions during neoadjuvant chemotherapy combined with immunotherapy, including four cases of CTCAE grade 3-4 adverse reactions resulting in bone marrow suppression and thoracic aortic thrombosis. All cases of adverse reactions were alleviated or disappeared after active symptomatic treatment. Among the 30 patients who underwent surgery, the time from chemotherapy combined with immunotherapy to surgery was 28 (23-49) days. All 30 patients underwent laparoscopic radical gastrectomy, of which 20 patients underwent laparoscopic-assisted radical gastric cancer resection; 10 patients underwent total gastrectomy for gastric cancer, combined with splenectomy in 1 case and cholecystectomy in 1 case. The surgery time was (239.9±67.0) min, intraoperative blood loss was 84 (10-400) ml, and the length of the incision was 7 (3-12) cm. The degree of adenocarcinoma was poorly differentiated in 18 cases, moderately differentiated in 12 cases, nerve invasion in 11 cases, and vascular invasion in 6 cases. The number lymph nodes that underwent dissection was 30 (17-58). The first of gas passage, the first postoperative defecation time, the postoperative liquid diet time, and the postoperative hospitalization time of 30 patients was 3 (2-6) d, 3 (2-13) d, 5 (3-12) d, and 10 (7-27) d, respectively. Postoperative complications occurred in 23 of 30 patients, including 7 cases of complications of Clavien-Dindo grade IIIa or above. Six patients improved after treatment and were discharged from hospital, while 1 patient died 27 days after surgery due to granulocyte deficiency, anemia, bilateral lung infection, and respiratory distress syndrome. The remaining 29 patients had no surgery-related morbidity or mortality within 30 days of discharge. Postoperative pathological examination showed TRG grades 0, 1, 2, and 3 in 8, 9, 4, and 9 cases, respectively, and the number of postoperative pathological TNM stages 0, I, II, and III was 8, 7, 8, and 7 cases, respectively. The pCR rate was 25.0% (8/32). Conclusion: Laparoscopic surgery after neoadjuvant SOX chemotherapy combined with PD-1 inhibitor immunotherapy for locally advanced gastric cancer is safe and feasible, with satisfactory short-term efficacy. Early detection and timely treatment of related complications are important.
Male ; Female ; Humans ; Middle Aged ; Aged ; Adolescent ; Young Adult ; Adult ; Stomach Neoplasms/pathology* ; Neoadjuvant Therapy ; Immune Checkpoint Inhibitors ; Gastrectomy/methods* ; Esophagogastric Junction/pathology* ; Laparoscopy ; Immunotherapy ; Postoperative Complications ; Retrospective Studies ; Treatment Outcome

Tyrosine kinase inhibitors (TKI) significantly reduce the risk of recurrence and metastasis and prolong survival in patients with gastrointestinal stromal tumors (GIST), but drug resistance is often inevitable. Immunotherapy has been proven effective in multiple solid tumors, but the efficacy in GIST is unclear. The efficacy of immunotherapy depends on the tumor microenvironment (TME). Tumor-infiltrating immune cells and immune checkpoints are important components of TME, which not only participate in the regulation of tumor immune response but are also the key target of immunotherapy. A comprehensive analysis of them can clarify the mechanism of tumor immune escape. This review found that there are abundant tumor-infiltrating immune cells in GIST, which play an important role in tumor immune surveillance and escape. Although early clinical studies have shown that patients with GIST have a good tolerance to immunotherapy, the curative effect is not satisfactory. Therefore, how to select the responders of immunotherapy and coordinate the relationship between immunotherapy and TKIs is the key issue to be explored. At the same time, the gradual deepening of basic research and large sample prospective clinical trials will certainly provide more strategies for the application of immunotherapy in GIST.
Humans ; Gastrointestinal Stromal Tumors/drug therapy* ; Prospective Studies ; Immunotherapy/methods* ; Tumor Microenvironment ; Protein Kinase Inhibitors/pharmacology*

This study aims to clarify host factors of IFN treatment in the treatment of chronic hepatitis B (CHB) patients by screening the differentially expressed genes of IFN pathway CHB patients with different response to interferon (IFN) therapy. Three cases were randomly selected in IFN-responding CHB patients (Rs), non-responding CHB patients (NRs) and healthy participants, respectively. The human type I IFN response RT ² profiler PCR array was used to detect the expression levels of IFN-related genes in peripheral blood monocytes (PBMCs) from healthy participants and CHB patients before and after Peg-IFN-α 2a treatment. The results showed that more differentially expressed genes appeared in Rs group than NRs group after IFN treatment. Comparing with healthy participants, IFNG, IL7R, IRF1, and IRF8 were downregulated in both Rs and NRs group before IFN treatment; CXCL10, IFIT1, and IFITM1 were upregulated in the Rs; IL13RA1 and IFI35 were upregulated in the NRs, while IFRD2, IL11RA, IL4R, IRF3, IRF4, PYHIN1, and ADAR were downregulated. The expression of IL15, IFI35 and IFI44 was downregulated by 4.09 ( t = 10.58, P < 0.001), 5.59 ( t = 3.37, P = 0.028) and 10.83 ( t = 2.8, P = 0.049) fold in the Rs group compared with the NRs group, respectively. In conclusion, IFN-response-related gene array is able to evaluate IFN treatment response by detecting IFN-related genes levels in PBMC. High expression of CXCL10, IFIT1 and IFITM1 before treatment may suggest satisfied IFN efficacy, while high expression of IL13RA1, IL15, IFI35 and IFI44 molecules and low expression of IFRD2, IL11RA, IL4R, IRF3, IRF4, PYHIN1 and ADAR molecules may be associated with poor IFN efficacy.
Humans ; Healthy Volunteers ; Hepatitis B, Chronic/genetics* ; Immunotherapy ; Interleukin-15 ; Leukocytes, Mononuclear ; Nuclear Proteins ; Oligonucleotide Array Sequence Analysis/methods* ; Interferons/therapeutic use* ; Treatment Outcome

Although the body has a strong immune system which can resists the invasion of leukemia cells, leukemia cells disseminate systemically and form an immunosuppressive microenvironment through a variety of mechanisms, including regulation of antigen presentation, utilization of immunosuppressive enzyme AXL, immune cell inhibitory checkpoint NKG2A and immunoregulatory gene VISTA, resulting in immune escape. Therefore, most types of leukemia are inevitable for the affliction of drug resistance or relapse, and the immune efficacy is not as significant as that of other hematological tumors and the prognosis is suboptimal. This article reviews the immune heterogeneity of leukemia microenvironment from many aspects, including anti-leukemia immunity and immune escape. In addition, it also reviews the latest progress and future prospects of immune checkpoint inhibition, adoptive cell therapy and vaccine therapy in leukemia, providing a theoretical basis for the development of personalized combination therapy strategies with less toxic side effects.
Humans ; Immunotherapy/methods* ; Leukemia/therapy* ; Immunity ; Combined Modality Therapy ; Prognosis ; Tumor Microenvironment

T-lymphocyte tumors are a group of diseases containing various types of lymphatic system tumors, with strong heterogeneity and poor clinical outcomes. Chimeric antigen receptor T (CAR-T) cell therapy, as a new immune cell therapy, has made a breakthrough in the field of B-lymphocyte tumors. People are interested in the application prospect of this technique in the field of T-lymphocyte tumors. Some studies have shown that CAR-T cell therapy has made some progress in the treatment of T-lymphocyte tumors, and CAR-T for some targets has entered the stage of clinical trials. However, due to the characteristics of T cells, there are also many challenges. This article reviews the research and application of CAR-T cell therapy in T-lymphocyte tumors.
Humans ; T-Lymphocytes ; Receptors, Chimeric Antigen/metabolism* ; Neoplasms/metabolism* ; Immunotherapy, Adoptive/methods* ; Cell- and Tissue-Based Therapy

With the development of medical technology, tumor vaccines as a novel precise immunotherapy approach have gradually received attention in clinical applications. Against the backdrop of the global corona virus disease 2019 (COVID-19) outbreak, vaccine technology has further advanced. Depending on the types of antigens, tumor vaccines can be divided into whole-cell vaccines, peptide vaccines, messenger ribonucleic acid (mRNA) vaccines, recombinant virus vaccines, etc. Although some tumor vaccines have been marketed and achieved certain therapeutic effects, the results of tumor vaccines in clinical trials have been unsatisfactory in the past period. With the maturation of next-generation sequencing (NGS) technology and the continuous development of bioinformatics, dynamic monitoring of the entire process of tumor subpopulation development has become a reality, which has laid a solid foundation for personalized, neoantigen-centered therapeutic tumor vaccines. This article reviews the recent developments of tumor vaccines of different types, starts with lung cancer and summarizes the achievements of tumor vaccines in clinical applications, and provides an outlook for the future development of antigen-centered tumor vaccines.
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Humans ; Cancer Vaccines/therapeutic use* ; Antigens, Neoplasm ; Lung Neoplasms/drug therapy* ; Neoplasms/genetics* ; Computational Biology ; Immunotherapy/methods* ; Lung

Immune checkpoint inhibitors (ICIs) have demonstrated unparalleled clinical responses and revolutionized the paradigm of tumor treatment, while substantial patients remain unresponsive or develop resistance to ICIs as a single agent, which is traceable to cellular metabolic dysfunction. Although dysregulated metabolism has long been adjudged as a hallmark of tumor, it is now increasingly accepted that metabolic reprogramming is not exclusive to tumor cells but is also characteristic of immunocytes. Correspondingly, people used to pay more attention to the effect of tumor cell metabolism on immunocytes, but in practice immunocytes interact intimately with their own metabolic function in a way that has never been realized before during their activation and differentiation, which opens up a whole new frontier called immunometabolism. The metabolic intervention for tumor-infiltrating immunocytes could offer fresh opportunities to break the resistance and ameliorate existing ICI immunotherapy, whose crux might be to ascertain synergistic combinations of metabolic intervention with ICIs to reap synergic benefits and facilitate an adjusted anti-tumor immune response. Herein, we elaborate potential mechanisms underlying immunotherapy resistance from a novel dimension of metabolic reprogramming in diverse tumor-infiltrating immunocytes, and related metabolic intervention in the hope of offering a reference for targeting metabolic vulnerabilities to circumvent immunotherapeutic resistance.
Humans ; Neoplasms/pathology* ; Immunotherapy/methods* ; Immune Checkpoint Inhibitors/therapeutic use*

As one of the most malignant tumors worldwide, lung cancer, fueled by metastasis, has shown rising mortality rates. However, effective clinical strategies aimed at preventing metastasis are lacking owing to its dynamic multi-step, complicated, and progressive nature. Immunotherapy has shown promise in treating cancer metastasis by reversing the immunosuppressive network of the tumor microenvironment. However, drug resistance inevitably develops due to inadequate delivery of immunostimulants and an uncontrolled immune response. Consequently, adverse effects occur, such as autoimmunity, from the non-specific immune activation and non-specific inflammation in off-target organs. Nanocarriers that improve drug solubility, permeability, stability, bioavailability, as well as sustained, controlled, and targeted delivery can effectively overcome drug resistance and enhance the therapeutic effect while reducing adverse effects. In particular, nanomedicine-based immunotherapy can be utilized to target tumor metastasis, presenting a promising therapeutic strategy for lung cancer. Nanotechnology strategies that boost the immunotherapy effect are classified based on the metastatic cascade related to the tumor immune microenvironment; the breaking away of primary tumors, circulating tumor cell dissemination, and premetastatic niche formation cause distant secondary site colonization. In this review, we focus on the opportunities and challenges of integrating immunotherapy with nanoparticle formulation to establish nanotechnology-based immunotherapy by modulating the tumor microenvironment for preclinical and clinical applications in the management of patients with metastatic lung cancer. We also discuss prospects for the emerging field and the clinical translation potential of these techniques.
Humans ; Lung Neoplasms/therapy* ; Tumor Microenvironment ; Neoplasms/drug therapy* ; Immunotherapy/methods*

In recent years, immunotherapy represented by immune checkpoint inhibitors programmed death 1 (PD-1) has made great progress in the treatment of esophageal cancer and is rewriting the global paradigm for the treatment of esophageal cancer. According to current data, only a small number of patients with esophageal cancer could benefit from immunotherapy. Therefore, it is a challenge to screen the potential beneficiaries of PD-1 inhibitors. Studies have shown that the expression level of programmed death-ligand 1 (PD-L1) in esophageal cancer is closely associated with the efficacy of PD-1 inhibitors, and PD-L1 is the most important predictive biomarker of the efficacy of PD-1 inhibitors. With the clinical application of different PD-1 inhibitors and PD-L1 protein expression detection platforms, clarifying the clinical significance and timing of detection of PD-L1 protein expression in esophageal cancer, and establishing a standardized PD-L1 testing procedure, are of great significance to improve the accuracy of detection and reduce the difference between laboratories, so as to maximize the therapeutic benefits for patients. This consensus was finally reached, based on the combination of literature, expert experience, and internal discussion and voting of committee members, to provide an accurate and reliable evidence for clinicians to make decisions.
Humans ; B7-H1 Antigen/metabolism* ; Immune Checkpoint Inhibitors/therapeutic use* ; Consensus ; Esophageal Neoplasms/drug therapy* ; Immunotherapy/methods* ; Lung Neoplasms/pathology*