Intrinsic Resistance of Solid Tumors to Immune Checkpoint Blockade Therapy

Abstract

Immune checkpoint blockade therapy (ICBT), which blocks negative immune-activating signals and maintains the antitumor response, has elicited a remarkable clinical response in certain cancer patients. However, intrinsic resistance (i.e., insensitivity of the tumors to therapy) remains a daunting challenge. The efficacy of ICBT is tightly modulated by the function of each step in the antitumor immunity cycle. Mechanistically, the number of mutations determines tumor immunogenicity. The properties of the tumor microenvironment control T-cell infiltration, distribution, and function in tumor tissues. Low tumor immunogenicity and a strong immunosuppressive tumor microenvironment cause significant intrinsic resistance to ICBT. With our evolving understanding of intrinsic resistance, people have successfully tested, in preclinical models, treatments targeting specific resistance mechanisms to sensitize ICBT-resistant tumors. Translation of those preclinical findings to the clinical arena will help generate personalized ICBT strategies that target tumor-specific resistance mechanisms. Progress in the new personalized ICBT strategies will expand the reach of immunotherapy to more cancer types, thus enabling more patients to benefit. .

Chemotherapy but not the tumor draining lymph nodes determine the immunotherapy response in secondary tumors

“…Immune checkpoint blockade therapies (ICBT), such as the FDA-approved anti-CTLA-4 antibody Ipilimumab, and anti-PD-1/PD-L1 antibodies Nivolumab and Atezolizumab, have transformed the therapeutic landscape of several site-specific cancer types including melanoma, and tumors of any primary site that harbor mismatch repair (MMR) deficiencies with microsatellite instability [1][2][3] . Nonetheless, as with more traditional forms of systemic chemotherapy options, many patients manifest either intrinsic or acquired resistance leading to treatment failure [4][5][6] . Multiple mechanisms have been delineated to influence tumor response to ICBTs, including the mutational load in tumor cells, degree of T cell exhaustion, tumor microenvironmental functions, and intestinal microbiota [4][5][6] .…”

“…Nonetheless, as with more traditional forms of systemic chemotherapy options, many patients manifest either intrinsic or acquired resistance leading to treatment failure [4][5][6] . Multiple mechanisms have been delineated to influence tumor response to ICBTs, including the mutational load in tumor cells, degree of T cell exhaustion, tumor microenvironmental functions, and intestinal microbiota [4][5][6] . In most case, ICBT is used for treating patients with heavily pretreated tumors; thus, the interactions between first-line therapy and beyond followed by ICBTs will potentially influence tumor response to ICBTs due to tumor evolution and heterogeneity.…”

Current status and perspectives of patient-derived xenograft models in cancer research

“…We recently evaluated new PD-1/PD-L1 antibodies in NSCLC PDX models established in humanized NSI mice reconstituted with human HSC or blood cells (unpublished). Nevertheless, intrinsic resistance to immune checkpoint inhibitors remains a daunting challenge [100]. PDX models can be used to evaluate treatments targeting specific resistance mechanisms to sensitize ICBT-resistant tumors.…”

In vitro and in vivo synergistic efficacy of ceritinib combined with programmed cell death ligand‐1 inhibitor in anaplastic lymphoma kinase‐rearranged non‐small‐cell lung cancer

“…The irAEs due to enhanced T cell reactivity and activation of self‐reactive T cells, such as common side‐effects (eg, fatigue, pruritus, and nausea) and life‐threatening pneumonitis, account for appropriate 14% in grade ≥3 level with broad organ system spectrum 17‐19 . Moreover, another aspect to be considered is that innate and acquired resistance, which prevent most cancer patients from reacting to PD‐1/PD‐L1 blockade, are major barriers to therapeutic application, and a large proportion of patients still face disease progression 19‐21 . Collectively, monotherapy using PD‐1/PD‐L1 blockade in a small proportion of patients with NSCLC shows limited outcomes, and it is indispensable to explore highly effective therapeutic approaches to overcome the weaknesses discussed above and maximize patients’ clinical benefit‐risk ratios.…”