Mechanisms of tumor resistance to immune checkpoint blockade and combination strategies to overcome resistance

Abstract

Immune checkpoint blockade (ICB) has rapidly transformed the treatment paradigm for various cancer types. Multiple single or combinations of ICB treatments have been approved by the US Food and Drug Administration, providing more options for patients with advanced cancer. However, most patients could not benefit from these immunotherapies due to primary and acquired drug resistance. Thus, a better understanding of the mechanisms of ICB resistance is urgently needed to improve clinical outcomes. Here, we focused on the changes in the biological functions of CD8⁺ T cells to elucidate the underlying resistance mechanisms of ICB therapies and summarized the advanced coping strategies to increase ICB efficacy. Combinational ICB approaches and individualized immunotherapies require further in-depth investigation to facilitate longer-lasting efficacy and a more excellent safety of ICB in a broader range of patients.

Keywords: T cell response; combination therapy; immune checkpoint blockade; immunotherapy; resistance mechanisms.

Figure 1

Mechanisms of ICB resistance from the perspective of immune response process. The success of ICB immunotherapy lies in the generation and/or reactivation of the population of CTL cells, which are also the central theme of immunotherapy. The left part of the picture depicts the normal immune response procedure which involves antigen processing and presentation, CD8⁺T cell priming, and the efficient killing of tumor cells by CTLs. Failure of immunotherapy occurs when the different phases of the cancer immunity cycle are compromised and blocked. There are numerous factors that decrease the effect of the antitumor immunity during the fight between tumor cells and immune cells. Regardless of the complexity of the immunotherapy resistance mechanisms, the consequence of these factors can be summarized as (A) failure of antigen recognition; (B) deficiency of antigen presentation; (C) poor CD8⁺ T cells infiltration and inhibited activity of CD8⁺ T cells; and (D) exhaustion of CD8⁺ T cells. Therefore, we focused on the immune response procedures, especially changes in biological function of CD8⁺T cells, with an aim to better understand the resistance mechanisms of ICB. The picture was created with BioRender.com. APC, antigen presentation cell; TAP, transporters associated with neoantigen presentation; ER, endoplasmic reticulum; MHC I, major histocompatibility complex class I; TCR, T cell receptor; CTL, cytotoxic T lymphocytes; TMB, tumor mutation burden; ITH, intra-tumor heterogeneity; DC, dendritic cell; TAM, tumor associated macrophages; CAF, cancer associated fibroblasts; TAN, tumor associated neutrophil; CTLA-4, cytotoxic T-lymphocyte antigen 4; VISTA, V-domain Ig suppressor of T cell activation; LAG-3, lymphocyte activation gene‐3; PD-1, programmed cell death protein -1; TIM-3, T-cell immunoglobulin mucin-3.

Figure 2

The crosstalk between CD8⁺T cells and the other suppressive cells within tumor microenvironment (TME). TME is infiltrated by different types of innate and adaptive immune cells. The complex crosstalk between these immune cells and tumor cells determines the immune status and the implementation of T cell function, thus to facilitate or inhibit the tumor response to ICBs. With the progression of malignant cells, immune cells within TME, for example, macrophages and neutrophils, are educated into pro-tumor cells. As such, TME becomes progressively immunosuppressive. Immunosuppressive cells inhibit the activity of T cells by upregulating immune checkpoints, capturing anti-PD-1 antibodies and secreting pro-tumor soluble factors such as arg-1, IL-10, TGF-β, promoting tumor immune evasion and resulting in resistance to checkpoint inhibitors. The picture was created with BioRender.com. CAF, cancer associated fibroblasts; TAN, Tumor associated neutrophil; TAM, Tumor associated macrophage; MDSC, myeloid-derived suppressor cell; PGE2, prostaglandin E2; GM-CSF, granulocyte-macrophages colony-stimulating factor; IDO, indoleamine 2,3-dioxygenase; TFR, follicle-regulating T cell.

Figure 3

Strategies reversing PD-1/PDL1 blockade by releasing tumor antigens (A) and enhancing antigen presentation (B). A.Chemotherapy, radiotherapy and oncolytic viruses could promote the immunogenic cell death (ICD), enhancing the liberation of immunogenic neoantigens, thus increasing the antigenicity in tumors resistant to ICB due to the failure of antigen recognition. In addition, some minimally invasive thermal ablation treatments lead to antigens release as well. (B) DNMTi, HDACi, HMTi epigenetically modulate the upregulation of MHC pathway. Stabilization of NF-κB, restoration of IFN signaling and induction of stimulator of interferon genes (STING) also reverse MHC-I downregulation. Besides, stimulation factors including cytokines such as FLT3L (FMS-like tyrosine kinase 3 ligand) and GM-CSF (granulocyte–macrophage colony-stimulating factor), Toll-like receptor (TLR2/TLR4, TLR3, TLR7/TLR8, TLR9) agonists, IDO inhibitors and STAT3 inhibitors could augment the infiltration, activation, and effector function of conventional DCs (cDCs), thus increasing antigen delivery. DC vaccines are also important tools boosting antigen presentation. The picture was created with BioRender.com. ICD, immunogenic cell death; STING, stimulator of interferon genes; FLT3L, FMS-like tyrosine kinase 3 ligand; GM-CSF, granulocyte–macrophage colony-stimulating factor; TLR, Toll-like receptor; IDO, indoleamine- (2,3)-dioxygenase; DC, dendritic cell.

Figure 4

Strategies overcoming resistance to PD-1/PDL1 by promoting T-cell infiltration (A), reversing T cell exhaustion (B), and CD8+ T cell stimulation (C). (A) methods promoting T-cell infiltration include targeted therapy, vascular-normalization therapies, CAR T therapy and low-dose radiotherapy; (B) treatment options to reinvigorate of T cell exhaustion include blocking the alternative immune checkpoints, targeting co-stimulatory receptors, inhibiting soluble immune suppressive mediators and epigenetically coordinating exhausted CD8+ T (Tex) cells. (C) strategies targeting immune-suppressive cells in TME such as TAM, Treg and CAF to stimulate T cells. In addition, radiotherapy and microbiota-centered interventions also reprogram the immunosuppressive TME, promoting antitumor T-cell responses. The picture was created with BioRender.com. CAR, chimeric antigen receptor, Treg, regulatory T lymphocytes; DC, dendritic cell; TAM, tumor associated macrophages; CAF, cancer associated fibroblasts; MARCO, macrophage receptor with collagenous structure; HRH1, histamine and histamine receptor H1.