This costimulatory signaling is associated with the tumor necrosis family receptors superfamily (TNFRSF). granzyme/perforin against effector T cells, and inhibit differentiation of effector T cells by IL-2 consumption by CD25. All of these functions provide immune suppressive environment. On the other hand, few effector T cells, which play essential roles in immune checkpoint therapy infiltrate into the tumor tissue. This imbalanced immune cells population tends to enhance immunosuppression and interrupt immune checkpoint therapy. The third possible reason is associated with stromal cells in the TME. An abundance of desmoplastic stroma is a distinctive feature of PAC. Desmoplastic stroma consists of cancer-associated fibroblasts (CAFs) and extracellular matrix (ECM) and immune cells. It is well known that CAFs promote tumor progression through the Hedgehog, Wnt/-catenin, Notch, K-ras signaling and the production of growth factors. In addition, CAFs secrete chemokine ligand 12 (CXCL12) and interleukin 17 (IL-17). These mediators suppress T cells chemokine receptor 4 (CXCR4). The CXCR4-CXCL12 axis may be related to resistance to immune checkpoint therapy because the blockade of this signal has a synergistic effect on anti-PD-1 therapy. As mentioned above, PAC induces a highly immunosuppressive environment regulated by immune cells, stromal cells, and mediators. This condition may contribute to its resistance to immune checkpoint therapy. OVERCOMING RESISTANCE TO IMMUNE CHECKPOINT THERAPY Comprehensive research studies have revealed strategies to overcoming the resistance to immune checkpoint therapy. One approach involves the establishment of a positive predictive biomarker for immune checkpoint therapy. Expression of PD-L1 may be one candidate predictive marker. In NCSLC, several trials have reported that the objective response rate is associated with PD-L1 expression, although conflicting evidence exists. However, as mentioned above, it is unclear whether the expression of PD-L1 could serve as a useful biomarker in patients with PAC. In addition, the standard immunohistochemical tests for the determination of PD-L1, and the cut off for PD-L1 positive status have not been established yet. Another candidate predictive marker is the mismatch repair (MMR) status of DNA. MMR deficiency leads to a high number of somatic mutations in tumors. Theoretically, accumulation of these somatic mutations can be recognized by the patients immune system. Le et al hypothesized that tumors with MMR deficiency are sensitive to immune checkpoint therapy, and initiated a phase 2 trial in which pembrolizumab was administered to 41 patients IMR-1A with or without MMR deficiency. In that trial, MMR status was assessed by microsatellite instability (MSI) analysis. Microsatellite is region of repetitive DNA, where hundreds to thousands of somatic mutations are occurred in tumor with MMR deficiency. Condition of accumulation of somatic mutations in microsatellite is referred to as MSI, and MSI reflects MMR deficiency. Of the 41 patients, 32 had colorectal cancers, which were regarded as immune resistant tumors. Eleven patients had MMR-deficient colorectal cancer and 21 had MMS-proficient forms. The remaining nine patients had MMR-deficient noncolorectal cancer. PAC was not included Efnb2 in the trial. They reported that the immune-related objective response was 40% in the patients with MMR deficiency, while patients without MMR deficiency did not achieved any response. Therefore, MMR status can be a useful predictive marker for pembrolizumab therapy. That is why PAC with MSI expects to be sensitive to PD-1 therapy. However, PAC with MSI is extremely rare and, therefore, this enrichment strategy based on IMR-1A MSI examination may not be realistic. Another approach to overcome the resistance to immune checkpoint therapy is establishment of more potent treatment. IMR-1A Combination immunotherapy is currently emerging as a promising treatment. However determining the most effective combinations is a challenge. Candidates for combination therapy with immune checkpoint inhibitors are (1) cytotoxic agents; (2) other immune checkpoint inhibitors; (3) direct cytotoxic T cell stimulators; (4) cancer vaccines; and (5) radiation (Tables ?(Tables11 and ?and2).2). Rationales and problems of each combination therapy are discussed here. Table 1 Rationales of each combination therapy thead align=”center” TreatmentsRationalesConcerns /thead Checkpoint inhibitor plus cytotoxic agentsEnhance cellular immunityEfficacy may be influenced by timing when cytotoxic agents addAugment dendritic cell maturationSevere myelosupression may interrupt immune checkpoint therapyReduce MDSC and TregsDecreases CAFCombination with checkpoint inhibitorsActivate tumor immunity by different mannarir AE will increaseProvide synergy efficacy even in immune resistant tumorCheckpoint inhibitor plus T cells stimulate agentsActivate tumor immunity by different mannarSevere AE including cytokine storm may occurDeactive TregsCheckpoint inhibitor plus cancer vaccineIncrease the presentation of taasEnhance PD-L1 expressionRadiotherapyEnhance cross priming of ctlsOptimal schedule and dose are not establishedEnhanse abscopal effect Open in a separate window MDSC: Myeloid-driven suppressor cell; CAF: Cancer-associated fibroblast; Tregs: Regulatory T cells. Table 2 Problems of each combination therapy thead align=”center” TreatmentDiseasePhaseClinical trial numberStatus /thead Checkpoint.