Impact of oncogenic pathways on evasion of antitumour immune responses

Abstract

Immunotherapeutic interventions are showing effectiveness across a wide range of cancer types, but only a subset of patients shows clinical response to therapy. Responsiveness to checkpoint blockade immunotherapy is favoured by the presence of a local, CD8⁺ T cell-based immune response within the tumour microenvironment. As molecular analyses of tumours containing or lacking a productive CD8⁺ T cell infiltrate are being pursued, increasing evidence is indicating that activation of oncogenic pathways in tumour cells can impair induction or execution of a local antitumour immune response. This Review summarizes our current knowledge of the influence of oncogenic effects on evasion of antitumour immunity.

Figure 1 |. Induction phase of a productive antitumour immune response.

From left to right: tumour cells produce CC-chemokine ligand 4 (CCL4), inducing the recruitment of basic leucine zipper transcriptional factor ATF-like 3 lineage dendritic cells (BATF3 DCs). BATF3 DCs sense the tumour and produce interferon α (IFNα) and IFNβ while migrating to the tumour-draining lymph node. Here, activated BATF3 DCs prime antigen-specific T cells, which subsequently home back into the tumour under the influence of CXC-chemokine ligand 9 (CXCL9) and CXCL10. Other chemokines (for example, CCL2) recruit other effector cells such as natural killer (NK) cells.

Figure 2 |. Impact of oncogenic signalling on immune inhibitory pathways and cell populations.

β-catenin: immune exclusion mediated by activation of the WNT–β-catenin pathway occurs when expression of CC-chemokine ligand 4 (CCL4) is inhibited and thus basic leucine zipper transcriptional factor ATF-like 3 lineage dendritic cells (BATF3 DCs) are no longer recruited into the tumour microenvironment. Consequently, owing to a lack of CXC-chemokine ligand 10 (CXCL10) production by BATF3 DCs, no T cell priming occurs, and effector T cells are not recruited into the tumour. MYC: activation of MYC signalling enhances the expression of leukocyte surface antigen CD47 and programmed cell death 1 ligand 1 (PDL1) on tumour cells through transcriptional regulation. Expression of these immune inhibitory molecules interferes with antigen uptake by antigen-presenting cells (APCs) via engagement with signal regulator protein-α (SIRPα) and inhibits T cell function via PD1 engagement, respectively. LKB1: loss of liver kinase B1 (LKB1) signalling within tumour cells results in increased expression of various cytokines, including interleukin-6 (IL-6), IL-33 and CXCL7. IL-6 mediates recruitment of neutrophils into the tumour microenvironment, an immunosuppressive cell type that contributes to reduced T cell infiltration and promotes T cell dysfunction. LKB1 mutations can also lead to activation of MYC signalling within the same tumour cells, providing potential crosstalk between pathways. PTEN: loss of PTEN protein function and thereby activation of PI3K inhibits lipidation of the autophagosome protein LC3 and autophagy in tumour cells, a process that can diminish T cell priming and also mediate resistance to T cell-mediated apoptosis. TP53: effector T cell exclusion from the tumour can occur owing to inactivating TP53 mutations, which results in reduced chemokine production by tumour cells. In particular, TP53-mutated tumour cells lack production of key chemokines required for the recruitment of natural killer (NK) cells and T cells, which is required for NK cell recruitment into the tumour microenvironment.