Adaptive Immunity and the Tumor Microenvironment

The adaptive immune response is a 500-million-year-old (the "Big Bang" of Immunology) collective set of rearranged and/or selected receptors capable of recognizing soluble and cell surface molecules or shape (B cells, antibody), endogenous and extracellular peptides presented by Major Histocompatibility (MHC) molecules including Class I and Class II (conventional αβ T cells), lipid in the context of MHC-like molecules of the CD1 family (NKT cells), metabolites and B7 family molecules/butyrophilins with stress factors (γδT cells), and stress ligands and absence of MHC molecules (natural killer, NK cells). What makes tumor immunogenic is the recruitment of initially innate immune cells to sites of stress or tissue damage with release of Damage-Associated Molecular Pattern (DAMP) molecules. Subsequent maintenance of a chronic inflammatory state, representing a balance between mature, normalized blood vessels, innate and adaptive immune cells and the tumor provides a complex tumor microenvironment serving as the backdrop for Darwinian selection, tumor elimination, tumor equilibrium, and ultimately tumor escape. Effective immunotherapies are still limited, given the complexities of this highly evolved and selected tumor microenvironment. Cytokine therapies and Immune Checkpoint Blockade (ICB) enable immune effector function and are largely dependent on the shape and size of the B and T cell repertoires (the "adaptome"), now accessible by Next-Generation Sequencing (NGS) and dimer-avoidance multiplexed PCR. How immune effectors access the tumor (infiltrated, immune sequestered, and immune desserts), egress and are organized within the tumor are of contemporary interest and substantial investigation.