Why the Outcome of Anti-Tumor Immune Responses is Heterogeneous: A Novel Idea in the Context of Immunological Heterogeneity in Cancers

Abstract

The question as to why some hosts can eradicate their tumors while others succumb to tumor-progression remains unanswered. Here, a provocative concept is proposed that intrinsic differences in the T cell receptor (TCR) repertoire of individuals may influence the outcome of anti-tumor immunity by affecting the frequency and/or variety of tumor-reactive CD8 and/or CD4 tumor-infiltrating lymphocytes. This idea implicates that the TCR repertoire in a given patient might not provide sufficiently different TCR clones that can recognize tumor antigens, namely, "a hole in the TCR repertoire" might exist. This idea may provide a novel perspective to further dissect the mechanisms underlying heterogeneous anti-tumor immune responses in different hosts. Besides tumor-intrinsic heterogeneity and host microbiome, the various factors that may constantly shape the dynamic TCR repertoire are also discussed. Elucidating mechanistic differences in different individuals' immune systems will allow to better harness immune system to design new personalized cancer immunotherapy.

Keywords: TCR repertoire; cancer immunology; heterogeneity of anti-tumor immunity; tumor immunogenicity.

Figure 1.. Mechanisms of action of immune checkpoint inhibitors.

(A) PD-1/PD-L1 interaction leads to exhaustion of CD4 and CD8 TILs. MHC class II or class I presents antigens to CD4 or CD8 T cells, respectively. PD-1 is expressed on activated CD4 or CD8 TILs, which can interact with PD-L1 expressed on cancer cells or other immune cells in the TME (e.g., myeloid cells). PD-1 engagement results in CD4 or CD8 TIL dysfunction. (B) Immune checkpoint inhibitors rescue CD4 or CD8 TILs. Anti-PD-1 or anti-PD-L1 blocks the interaction between PD-1/PD-L1, thereby leading to the reactivation of CD4 or CD8 TILs.

Figure 2.. Overview of T cell development and V(D)J recombination.

(A) V(D)J recombination during T cell development. TCRβ gene rearrangement occurs in double negative (DN) (CD4⁻CD8⁻) progenitor T cell (Pro T) population. TCRα gene rearrangement occurs in double positive (DP) (CD4⁺CD8⁺) pre-T cell population. CD4 or CD8 SP immature T cells undergo thymic selection before their emigration of thymus. In peripheral lymphoid organs, 95% of human T cells are αβ T cells, whereas about 5% of human T cells are γδ T cells. (B) Schematics of V(D)J recombination in TCRβ locus. Top: germline configuration of human TCRβ locus. RAGs (recombination activating genes) initiate V(D)J recombination by generating DNA breaks at the V, D or J gene segments. Non-homologous end-joining (NHEJ) DNA repair pathway joins the broken V, D, J gene segments and completes V(D)J recombination.