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The majority of lung cancer patients progressing from conventional therapies are refractory to PD‐L1/PD‐1 blockade monotherapy. Here, we show that baseline systemic CD4 immunity is a differential factor for clinical responses. Patients with functional systemic CD4 T cells included all objective responders and could be identified before the start of therapy by having a high proportion of memory CD4 T cells. In these patients, CD4 T cells possessed significant proliferative capacities, low co‐expression of PD‐1/LAG‐3 and were responsive to PD‐1 blockade ex vivo and in vivo . In contrast, patients with dysfunctional systemic CD4 immunity did not respond even though they had lung cancer‐specific T cells. Although proficient in cytokine production, CD4 T cells in these patients proliferated very poorly, strongly co‐upregulated PD‐1/LAG‐3, and were largely refractory to PD‐1 monoblockade. CD8 immunity only recovered in patients with functional CD4 immunity. T‐cell proliferative dysfunctionality could be reverted by PD‐1/LAG‐3 co‐blockade. Patients with functional CD4 immunity and PD‐L1 tumor positivity exhibited response rates of 70%, highlighting the contribution of CD4 immunity for efficacious PD‐L1/PD‐1 blockade therapy. Synopsis Lung cancer patients are often refractory to PD‐L1/PD‐1 blockade therapy. This study shows that patients progressing from conventional therapies that have functional CD4 T cells respond to PD‐L1/PD‐1 blockade immunotherapy, while patients with proliferative dysfunctional CD4 T cells do not respond. Functional systemic CD4 immunity is required for objective clinical responses to PD‐L1/PD‐1 blockade therapy in human lung cancer patients. Systemic memory CD4 T cells identify intrinsic non‐responder from potentially responder patients. 70% of patients with high baseline percentages of memory CD4 T cells and PD‐L1‐positive tumors respond to therapy. Proliferative CD4 dysfunctionality in non‐responder patients can be overcome by PD‐1/LAG‐3 co‐blockade. Graphical Abstract Lung cancer patients are often refractory to PD‐L1/PD‐1 blockade therapy. This study shows that patients progressing from conventional therapies that have functional CD4 T cells respond to PD‐L1/PD‐1 blockade immunotherapy, while patients with proliferative dysfunctional CD4 T cells do not respond.

There is an urgent need to develop new life‐prolonging therapy for pancreatic ductal adenocarcinoma (PDAC). It is demonstrated that improved irinotecan delivery by a lipid bilayer coated mesoporous silica nanoparticle, also known as a silicasome, can improve PDAC survival through a chemo‐immunotherapy response in an orthotopic Kras‐dependent pancreatic cancer model. This discovery is premised on the weak‐basic properties of irinotecan, which neutralizes the acidic lysosomal pH in PDAC cells. This effect triggers a linked downstream cascade of events that include autophagy inhibition, endoplasmic reticulum stress, immunogenic cell death (ICD), and programmed death‐ligand 1 (PD‐L1) expression. ICD is characterized by calreticulin expression and high‐mobility group box 1 (HMGB1) release in dying Kras‐induced pancreatic cancer (KPC) cells, which is demonstrated in a vaccination experiment to prevent KPC tumor growth on the contralateral site. The improved delivery of irinotecan by the silicasome is accompanied by robust antitumor immunity, which can be synergistically enhanced by anti‐PD‐1 in the orthotopic model. Immunophenotyping confirms the expression of calreticulin, HMGB1, PD‐L1, and an autophagy marker, in addition to perforin and granzyme B deposition. The chemo‐immunotherapy response elicited by the silicasome is more robust than free or a liposomal drug, Onivyde. The silicasome plus anti‐PD‐1 leads to significantly enhanced survival improvement, and is far superior to anti‐PD‐1 plus either free irinotecan or Onivyde. Improved irinotecan delivery by silicasome can improve pancreatic ductal adenocarcinoma (PDAC) survival through a chemo‐immunotherapy response when combined with anti‐PD‐1 in an orthotopic Kras‐dependent PDAC model. This discovery is premised on the weak‐basic properties of irinotecan, which neutralizes the acidic lysosomal pH and triggers a linked downstream cascade of events that include autophagy inhibition, endoplasmic reticulum stress, immunogenic cell death, and PD‐L1 expression.

Immunocheckpoint proteins of tumor infiltrating lymphocytes play an important role in tumor prognosis in the course of tumor clinicopathology. PD‐1 (Programmed cell death protein 1) is an important immunosuppressive molecule. By binding to PD‐L1 (programmed cell death‐ligand 1), it blocks TCR and its costimulus signal transduction, inhibits the activation and proliferation of T cells, depletes the function of effector T cells, and enables tumor cells to achieve immune escape. In recent years, immunocheckpoint blocking therapy targeting the PD‐1/PD‐L1 axis has achieved good results in a variety of malignant tumors, pushing tumor immunotherapy to a new milestone, such as anti‐PD‐1 monoclonal antibody Nivolumab, Pembrolizumab, and anti‐PD‐L1 monoclonal antibody Atezolizumab, which are considered as potential antitumor drugs. It was found in clinical use that some patients obtained long‐term efficacy, but most of them developed drug resistance recurrence in the later stage. The high incidence of drug resistance (including primary and acquired drug resistance) still cannot be ignored, which limited its clinical application and became a new problem in this field. Due to tumor heterogeneity, current limited research shows that PD‐1 or PD‐L1 monoclonal antibody drug resistance may be related to the following factors: mutation of tumor antigen and antigen presentation process, multiple immune checkpoint interactions, immune microenvironment changes dynamically, activation of oncogenic pathways, gene mutation and epigenetic changes of key proteins in tumors, tumor competitive metabolism, and accumulation of metabolites, etc, mechanisms of resistance are complex. Therefore, it is the most urgent task to further elucidate the mechanism of immune checkpoint inhibitor resistance, discover multitumor universal biomarkers, and develop new target agents to improve the response rate of immunotherapy in patients. In this study, the mechanism of anti‐PD‐1/PD‐L1 drug resistance in tumors, the potential biomarkers for predicting PD‐1 acquired resistance, and the recent development of combination therapy were reviewed one by one. It is believed that, based on the complex mechanism of drug resistance, it is of no clinical significance to simply search for and regulate drug resistance targets, and it may even produce drug resistance again soon. It is speculated that according to the possible tumor characteristics, three types of treatment methods should be combined to change the tumor microenvironment ecology and eliminate various heterogeneous tumor subsets, so as to reduce tumor drug resistance and improve long‐term clinical efficacy. Based on the analysis of existing studies, ICB resistance involves complex network regulatory mechanisms, and the countermeasures against certain drug resistance mechanisms cannot solve the drawbacks of clinical drug resistance. In terms of treatment, traditional basic treatment, evidence‐based treatment of tumor type, and individual precision therapy should be integrated to comprehensively remove all subsets of cells in heterogeneous tumors.

PD‐1/PD‐L1 immune checkpoint inhibitors are promising cancer immunotherapies however responses are still limited and the development of more effective combination immunotherapy is needed. We previously reported that STAT3 activation in cancer cells and immune cells was involved in immune‐resistant mechanisms. In this study, we evaluated the effect of highly absorptive forms of curcumin extracts and synthetic curcumin on anti‐tumor T cell responses. The curcumin po administration resulted in the significant augmentation of in vivo induction of tumor antigen‐specific T cells through restoration of dendritic cells (DCs) by inhibiting directly STAT3 in DCs and indirectly via reduced IL‐6 production from STAT3 activated cancer cells in 2 syngeneic MC38 and CT26 murine tumor models. Curcumin also showed direct DC enhancing activity and enhanced T cell induction for the immunized antigens in non‐tumor‐bearing mice and human hosts. Curcumin restored DC functions in xenogeneic nude mouse model implanted with high IL‐6‐producing human clear cell ovarian cancer cells. The combination of curcumin and PD‐1/PD‐L1 Abs demonstrated a synergistic anti‐tumor activity in MC38 murine tumor models. These results indicated that curcumin augments the induction of tumor antigen‐specific T cells by restoring the T cell stimulatory activity of DCs targeting activated STAT3 in both cancer cells and immune cells. Combination immunotherapy with curcumin and PD‐1/PD‐L1 Ab is an attractive strategy in the development of effective immunotherapy against various cancers. Highly absorptive form of curcumin can restore the T cell stimulatory activity of DCs and augment the induction of tumor antigen‐specific T cells by targeting activated STAT3 in both cancer cells and immune cells. Combination immunotherapy with curcumin and PD‐1/PD‐L1 Ab is an attractive strategy in the development of effective immunotherapy against various cancers.

Objectives Although targeted therapy has revolutionized the treatment of gastrointestinal stromal tumours (GIST), it is almost never curative in GIST, and resistance commonly develops. One potential strategy is to combine targeted therapy with immunotherapy. Materials and methods We first studied Programmed cell death 1 ligand 1 (PD‐L1) expression and tumour‐infiltrating T cells (TILs) in GIST. IFN‐γ was used to induce the upregulation of PD‐L1 expression in GIST‐882 cells, a well‐known GIST cell line. CD8+ T‐cell apoptosis was determined by flow cytometry. The PI3K/Akt/mTOR levels in CD8+ T cells were examined by Western blotting. Results PD‐L1 expression was an independent factor of poor prognosis in GIST and resulted in exhausted T cells in the TILs population or the blood. Then, we found that PD‐L1 blockade alone could not increase tumour cell apoptosis in GIST. The apoptosis rate of CD8+ T cells was higher when T cells were cultured with PD‐L1+ GIST‐882 cells (GIST‐882 cells with high PD‐L1 expression) than when T cells were cultured with control GIST‐882 cells. However, when the PD‐L1 blockade was used, the apoptosis rates of the CD8+ T cells in the two groups became similar. Then, Western blotting showed the PI3K/Akt/mTOR levels of the CD8+ T cells rescued by the PD‐1/PD‐L1 blockade were higher than those of the CD8+ T cells not treated with the PD‐1/PD‐L1 blockade. Conclusions PD‐L1 expression was an independent poor prognosis factor in GIST. PD‐1/PD‐L1 blockade rescued exhausted CD8+ T cells in GIST via the PI3K/Akt/mTOR signalling pathway. In GIST, PD‐1/PD‐L1 not only function as predictive biomarkers but also improve current therapies as treatment targets.

Summary Immune checkpoint blocking therapy targeting the PD‐1/PD‐L1 inhibitory signalling pathway has produced encouraging results in the treatment of a variety of cancers. Durvalumab (Imfinzi®) targeting PD‐L1 is currently used for immunotherapy of several tumour malignancies. The Fc region of this IgG1 antibody has been engineered to reduce FcγR interactions with the aim of enhancing blockade of PD‐1/PD‐L1 interactions without the depletion of PD‐L1‐expressing immune cells. Here, we used Nicotiana benthamiana to produce four variants of Durvalumab (DL): wild‐type IgG1 and its ‘Fc‐effector‐silent’ variant (LALAPG) carrying further modifications to increase antibody half‐life (YTE); IgG4S228P and its variant (PVA) with Fc mutations to decrease binding to FcγRI. In addition, DL variants were produced with two distinct glycosylation profiles: afucosylated and decorated with α1,6‐core fucose. Plant‐derived DL variants were compared to the therapeutic antibody regarding their ability to (i) bind to PD‐L1, (ii) block PD‐1/PD‐L1 inhibitory signalling and (iii) engage with the neonatal Fc receptor (FcRn) and various Fcγ receptors. It was found that plant‐derived DL variants bind to recombinant PD‐L1 and to PD‐L1 expressed in gastrointestinal cancer cells and are able to effectively block its interaction with PD‐1 on T cells, thereby enhancing their activation. Furthermore, we show a positive impact of Fc amino acid mutations and core fucosylation on DL's therapeutic potential. Compared to Imfinzi®, DL‐IgG1 (LALAPG) and DL‐IgG4 (PVA)S228P show lower affinity to CD32B inhibitory receptor which can be therapeutically favourable. Importantly, DL‐IgG1 (LALAPG) also shows enhanced binding to FcRn, a key determinant of serum half‐life of IgGs.

Immune checkpoint inhibitor discovery represents a turning point in cancer treatment. However, the response rates of solid tumors remain ~10%–30%; consequently, prognostic and immune‐related adverse event (irAE) predictors are being explored. The programmed cell death protein 1 (PD‐1) receptor occupancy (RO) of PD‐1 inhibitors depends on the number of peripheral blood lymphocytes and their PD‐1 expression levels, suggesting that the RO may be related to efficacy and adverse events. As PD‐1 inhibition affects each T‐cell subset differently, the RO of each cell population must be characterized. However, relevant data have not been reported, and the prognostic relevance of this parameter is not known. In this study, we aimed to clarify the association between the nivolumab RO in each T‐cell population and patient prognosis and reveal the development of irAEs in nivolumab‐treated patients. Thirty‐two patients were included in the study, and the mean follow‐up period was 364 days. The nivolumab RO on effector regulatory T cells (eTregs) was significantly lower in the group that presented clinical benefits, and a significant negative association was observed between PD‐1 occupancy on eTregs and all‐cause mortality. The results suggest that the nivolumab RO on eTregs may be a prognostic factor in PD‐1 inhibitor therapy, implying that the inhibition of PD‐1/PD‐ligand 1 (PD‐L1) signaling on eTregs may attenuate antitumor effects. Measurement of PD‐1 receptor occupancy. PBMCs were saturated with either unlabeled human IgG4 (isotype control) or nivolumab and then co‐stained with murine anti‐human IgG4 biotin plus streptavidin‐phycoerythrin.

Immune checkpoint inhibitor (ICI) therapies for tumors of different systems have attained significant achievements and have changed the current situation of tumor treatment due to their therapeutic characteristics of high specificity and low side effects. The immune checkpoint Programmed death 1/Programmed cell death‐Ligand 1 (PD‐1/PD‐L1) axis exerts a vital role in the immune escape of tumor cells. As a result, it has become a key target for tumor immunotherapy. Therefore, to perfect research into potential regulatory factors for the PD‐1/PD‐L1 axis, in order to understand and illustrate tumor ICI therapy mechanisms, is a significant goal. Moreover, ncRNA has been verified to regulate the PD‐1/PD‐L1 axis in the tumor immune microenvironment to regulate tumor genesis and development. ncRNAs can improve or decrease the efficacy of ICI therapy by modulating PD‐L1 expression. This review aimed to investigate the mechanisms of action of ncRNA in regulating the PD‐1/PD‐L1 axis in ICI therapy, to provide more efficient immunotherapy for tumors of different systems. Immune checkpoint inhibitor therapy can decrease the occurrence and development of cancer by inhibiting PD‐1, PD‐L1, CTLA‐4 and other immune checkpoint molecules. ncRNAs can interfere with the PD‐1/PD‐L1 axis of immune checkpoint inhibitor therapy by binding to the mRNA of PD‐L1, thus affecting the immune escape process of cancer cells.

Immune checkpoint inhibitors have been associated with long-term complete responses leading to improved overall survival in several cancer types. However, these novel immunotherapies are only effective in a small proportion of patients, and therapeutic resistance represents a major limitation in clinical practice. As with chemotherapy, there is substantial evidence that radiation therapy promotes anti-tumor immune responses that can enhance systemic responses to immune checkpoint inhibitors. In this review, we discuss the main preclinical and clinical evidence on strategies that can lead to an enhanced response to PD-1/PD-L1 blockade in combination with radiation therapy. We focused on central issues in optimizing radiation therapy, such as the optimal dose and fractionation for improving the therapeutic ratio, as well as the impact on immune and clinical responses of dose rate, target volume, lymph nodes irradiation, and type of radiation particle. We explored the addition of a third immunomodulatory agent to the combination such as other checkpoint inhibitors, chemotherapy, and treatment targeting the tumor microenvironment components. The strategies described in this review provide a lead for future clinical trials.

The human gastrointestinal (GI) tract harbors gut microbiome, which plays a crucial role in preserving homeostasis at the intestinal host‐microbial interface. Conversely, specific gut microbiota may be altered during various pathological conditions and produce a number of toxic compounds and oncoproteins, in turn, to induce both inflammatory response and carcinogenesis. Recently, promising findings have been documented toward the implementation of certain intestinal microbiome in the next era of cancer biology and cancer immunotherapy. Notably, intestinal microbiota can cooperate with immune checkpoint inhibitors (ICIs) of its host, especially in enhancing the efficacy of programmed death 1 (PD‐1) protein and its ligand programmed death ligand 1 (PD‐L1) blockade therapy for cancer. Herein, we review the dual function of gut microbiota in triggering GI cancers, its association with host immunity and its beneficial functions in modulation of cancer immunotherapy responses. Furthermore, we consider the significance of gut microbiota as a potential biomarker for predicting the efficacy of cancer immunotherapy. Finally, we summarize the relevant limitations that affect the effectiveness and clinical applications of gut microbiome in response to immunotherapy. In this review, we discuss the dual role of gut microbiome in triggering GI cancers, its association with host immunity and its beneficial functions in modulation of cancer immunotherapy responses. Furthermore, we consider the significance of gut microbiota as a potential biomarker for predicting the response to immunotherapy.