Shifting the paradigm: engaging multicellular networks for cancer therapy

Abstract

Most anti-cancer modalities are designed to directly kill cancer cells deploying mechanisms of action (MOAs) centered on the presence of a precise target on cancer cells. The efficacy of these approaches is limited because the rapidly evolving genetics of neoplasia swiftly circumvents the MOA generating therapy-resistant cancer cell clones. Other modalities engage endogenous anti-cancer mechanisms by activating the multi-cellular network (MCN) surrounding neoplastic cells in the tumor microenvironment (TME). These modalities hold a better chance of success because they activate numerous types of immune effector cells that deploy distinct cytotoxic MOAs. This in turn decreases the chance of developing treatment-resistance. Engagement of the MCN can be attained through activation of immune effector cells that in turn kill cancer cells or when direct cancer killing is complemented by the production of proinflammatory factors that secondarily recruit and activate immune effector cells. For instance, adoptive cell therapy (ACT) supplements cancer cell killing with the release of homeostatic and pro-inflammatory cytokines by the immune cells and damage associated molecular patterns (DAMPs) by dying cancer cells. The latter phenomenon, referred to as immunogenic cell death (ICD), results in an exponential escalation of anti-cancer MOAs at the tumor site. Other approaches can also induce exponential cancer killing by engaging the MCN of the TME through the release of DAMPs and additional pro-inflammatory factors by dying cancer cells. In this commentary, we will review the basic principles that support emerging paradigms likely to significantly improve the efficacy of anti-cancer therapy.

Fig. 1

– Direct vs indirect models for cancer cell elimination. A Linear model of direct cancer cell killing; by targeting a specific attribute of cancer cells that differentiate them from benign cells exemplified here by a traditional small molecule directed against a cancer-driving pathway or a biological binder directed against an antigen that can be recognized on the surface of cancer cells. Cancer elimination depends solely on the linear relationship between the mechanism of action (MOA) and the relevance of its target. Cancer cells that eliminate the target become resistant to therapy. B Exponential model of direct cancer cell killing; Therapies including ‘smart’ small molecules, biologics such as ADCs, CAR T cells and TILs, and genetic payloads can induce cancer cell death and the release of tumor-associated antigens (Ags) and damage associated molecular factors (DAMPs) perceived as abnormal by the multicellular network (MCN) in the tumor microenvironment (TME), thus initiating a mechanism referred to as immunogenic cell death (ICD). This elicits the recruitment of immune cells in the TME that can lead to further cancer killing dependent on additional MOAs distinct from the original one. Complex therapeutics such as activated immune effector cells delivered through adoptive cell therapy (ACT), can add the secretion of homeostatic cytokines such as interleukin (IL)-2 that sustain their persistence and proinflammatory cytokines such as interferon (IFN)-$\gamma$ and tumor necrosis factor (TNF)-α that can redirect an immune suppressive cellular network into one hostile to cancer cell survival. This can further escalated by the delivery of genetic information that induces the production of genes not normally produced by immune effector cells such as IL-15, IL-12, IL-18, that further amplify the anti-cancer cell reaction by recruiting additional immune effector mechanisms that employ additional MOAs. C Linear model of indirect cancer killing: the therapeutic targets a specific function of a cellular component of the multicellular network in the TME through a single MOA. Here exemplified by a mAb targeting a checkpoint receptor such as programmed cell death protein 1 (PD1) present on the surface of immune effector cells, in particular CD8⁺ antigen-specific T cells, allows for proliferation and stabilization of  function. Since the resident CD8⁺ T cells recognize different Ags, the anti-cancer response is amplified by recognizing multiple targets relevant to the specific TME compared to biologics that target a predetermined Ags. D Conditional exponential model of indirect cancer killing: “if” successful indirect cancer killing can ignite the exponential model described in B). However, the indirect approach depends on the presence of PD1 expressing CD8⁺ T cells in the TME and the weight that PD1 plays over other mechanism of immune suppression. This concept applies to all methods targeting a benign component of the TME based on a single MOA