Modulation of APC Function and Anti-Tumor Immunity by Anti-Cancer Drugs

Abstract

Professional antigen-presenting cells (APCs), such as dendritic cells (DCs), are central to the initiation and regulation of anti-cancer immunity. However, in the immunosuppressive environment within a tumor APCs may antagonize anti-tumor immunity by inducing regulatory T cells (Tregs) or anergy of effector T cells due to lack of efficient costimulation. Hence, in an optimal setting, anti-cancer drugs have the power to reduce tumor size and thereby may induce the release of tumor antigens and, at the same time, modulate APC function toward efficient priming of antigen-specific effector T cells. Selected cytotoxic agents may revert APC dysfunction either by directly maturing DCs or through induction of immunogenic tumor cell death. Furthermore, specific cytotoxic agents may support adaptive immunity by selectively depleting regulatory subsets, such as Tregs or myeloid-derived suppressor cells. Perspectively, this will allow developing effective combination strategies with novel immunotherapies to exert complementary pressure on tumors via direct toxicity as well as immune activation. We, here, review our current knowledge on the capacity of anti-cancer drugs to modulate APC functions to promote durable anti-cancer immune responses.

Acetazolamide Serves as Selective Delivery Vehicle for Dipeptide-Linked Drugs to Renal Cell Carcinoma

“…It has recently been shown that certain cytotoxic agents can mediate an immunogenic tumor cell death [44,45]. In addition, certain immunostimulatory agents (e.g., antibody-cytokine fusion proteins, immunological check-point inhibitors) may potently synergize with some cytotoxic agents [46][47][48].…”

Antibody–Drug Conjugates (ADCs) for Personalized Treatment of Solid Tumors: A Review

“…Not only do such ADCs induce immunogenic cell death, but the ADC-mediated tumor accumulation of a potent microtubule agent appears to activate intra-tumor dendritic cells, inducing uptake of antigens and the migration of antigen-loaded dendritic cells to lymph nodes where they can trigger activation of T-cells which may be directed towards tumor-associated antigens [92–95]. Pre-clinically, Müller et al have demonstrated that T-DM1 renders HER2-positive breast cancer highly susceptible to checkpoint blockade [94].…”

Combination Approaches with Immune-Checkpoint Blockade in Cancer Therapy

“…ICD results in the release of tumor antigens and “danger signals,” also known as damage-associated molecular patterns (DAMPS), such as calreticulin, ATP, type I IFN, and non-histone chromatin-binding protein high-mobility group box 1 (HMGB1) (30, 31). Binding to their receptors (CD91, the purinergic receptors P2RX7 and P2RY2, IFNAR, and the toll-like receptor TLR4, respectively) on DCs, results in their activation, enhanced antigen presentation, upregulation of co-stimulatory receptors, and induction of adaptive immune responses (32), whereas cell death that is “immunologically silent” induces tolerance.…”