Primary, Adaptive, and Acquired Resistance to Cancer Immunotherapy

Abstract

Cancer immunotherapy can induce long lasting responses in patients with metastatic cancers of a wide range of histologies. Broadening the clinical applicability of these treatments requires an improved understanding of the mechanisms limiting cancer immunotherapy. The interactions between the immune system and cancer cells are continuous, dynamic, and evolving from the initial establishment of a cancer cell to the development of metastatic disease, which is dependent on immune evasion. As the molecular mechanisms of resistance to immunotherapy are elucidated, actionable strategies to prevent or treat them may be derived to improve clinical outcomes for patients.

Keywords: T cells; immunotherapy; resistance mechanisms.

Figure 1. Clinical scenarios of primary, adaptive and acquired resistance to immunotherapy

A) Patient’s tumor is resistant to immunotherapy with no active immune response. B) Patient’s tumor is resistant to immunotherapy; active anti-tumor immune response but turned off by checkpoints or other adaptive resistance mechanisms. C) Patient has an initial response to immunotherapy but later progressed – heterogeneous population and selection of resistant clones that were present before treatment started. D) Patient has an initial response to immunotherapy but later progressed, true acquired resistance during the immunotherapy.

Figure 2. Known intrinsic mechanisms of resistance to immunotherapy

A) Intrinsic factors that lead to primary or adaptive resistance including lack of antigenic mutations, loss of tumor antigen expression, loss of HLA expression, alterations in antigen processing machinery, alterations of several signaling pathways (MAPK, PI3K, WNT, IFN) and constitutive PD-L1 expression. B) Intrinsic factors that are associated with acquired resistance of cancer, including loss of target antigen, HLA, altered interferon signaling, as well as loss of T cell functionality.

Figure 3. Known extrinsic mechanisms of resistance to immunotherapy

This includes CTLA-4, PD1 and other immune checkpoints, T cell exhaustion and phenotype change, immune suppressive cell populations (Tregs, MDSC, type II macrophages), cytokine and metabolite release in the tumor microenvironment (CSF-1, tryptophan metabolites, TGFβ, adenosine). LN: lymph node; TME: tumor microenvironment; APC: antigen presenting cells; MHC: major histocompatibility complex; TCR: T cell receptor; TLR: toll like receptor; Treg: regulatory T cell; MDSC: myeloid-derived suppressor cell; Mϕ II: type II macrophage.

Figure 4. Schema for analysis of baseline and longitudinal tumor, blood, and other samples

A) Baseline assessment of the tumor microenvironment typically involves molecular analysis for mutational load, driver mutations and gene expression, with immune profiling including analysis of CD8+ T cells, PD-L1 expression, and T cell clonality. B) Longitudinal evaluation of fresh serial human specimens (tumor, blood, serum, and microbiome) during treatment (at pre-treatment, early on-treatment, and progression time points) allows for deep analysis to unveil potential mechanisms of therapeutic resistance.