Immune evasion in cell-based immunotherapy: unraveling challenges and novel strategies

Abstract

Cell-based immunotherapies (CBIs), notably exemplified by chimeric antigen receptor (CAR)-engineered T (CAR-T) cell therapy, have emerged as groundbreaking approaches for cancer therapy. Nevertheless, akin to various other therapeutic modalities, tumor cells employ counterstrategies to manifest immune evasion, thereby circumventing the impact of CBIs. This phenomenon is facilitated by an intricately immunosuppression entrenched within the tumor microenvironment (TME). Principal mechanisms underpinning tumor immune evasion from CBIs encompass loss of antigens, downregulation of antigen presentation, activation of immune checkpoint pathways, initiation of anti-apoptotic cascades, and induction of immune dysfunction and exhaustion. In this review, we delve into the intrinsic mechanisms underlying the capacity of tumor cells to resist CBIs and proffer prospective stratagems to navigate around these challenges.

Keywords: CAR-engineered T (CAR-T) cell therapy; Cell-based immunotherapies (CBIs); Chimeric antigen receptor (CAR); Immune checkpoint proteins; Immune evasion; Tumor heterogeneity; Tumor microenvironment (TME).

Fig. 1

Mechanisms of tumor immune evasion. Tumor cells employ a diverse array of immune evasion mechanisms that curtail the effectiveness of cell-based immunotherapies, such as CAR-T cell therapies. These multifaceted strategies encompass tumor heterogeneity (A), tumor antigen loss (B), antigen presentation downregulation (C), immune checkpoint activation (D), apoptosis resistance (E), antigen masking (F), tumor lineage switch (G), tumor-induced immunosuppression (H), tumor microenvironment (TME) immunosuppression (I), and induction of T cell exhaustion (J)

Fig. 2

Engineering strategies to overcome immune evasion. Innovative engineering strategies have been deployed to substantially enhance the recognition of tumors, the durability of therapeutic cells, their ability to infiltrate the tumor microenvironment, and the overall effectiveness of cellular therapies. These strategies encompass a range of techniques, including the incorporation of multiple targeting mechanisms (A), fortifying therapeutic cells with cytokines (B), modifying the immunosuppressive tumor microenvironment (C), amplifying cell infiltration capabilities (D), and employing combination therapies (E). TanCAR, tandem CAR; iNKT, invariant natural killer T; MAIT, mucosal associated invariant T; γδ T, gamma delta T; ICB, immune checkpoint inhibitor; ECM, extracellular matrix

Fig. 3

Biomarkers for cell-based immunotherapy. Biomarkers have emerged as invaluable tools in the realm of immunology and cancer therapy, playing a pivotal role in predicting several critical aspects of the immune response. Specifically, these biomarkers have found widespread application in forecasting immune cell exhaustion, a state where immune cells lose their functionality and become less effective in combating diseases. Moreover, they contribute to the anticipation of immune cell differentiation, providing insights into how immune cells transform into specialized subsets with distinct functions. Biomarkers are also instrumental in predicting the onset of cytokine release syndrome (CRS), a potentially severe immune-related side effect of certain therapies. Additionally, they aid in the assessment of the tumor microenvironment (TME), offering crucial information about the dynamic interplay between immune cells and the tumor, which is indispensable for designing personalized and effective treatment strategies