Sunday, October 6, 2024
10/6/2024
Priming of antitumor immunity relies on a specialized subset of conventional Dendritic Cells (cDC1s), CD103+ DCs, that have unique capabilities of trafficking tumor antigens to lymph nodes for cross-presentation. The critical role of cDC1s in cancer immune surveillance make them highly coveted targets for immunotherapy; however, their scarcity, the difficulty of specifically engaging DCs, and the suppressive tumor microenvironment (TME) pose severe obstacles. We are investigating immunotherapy with attenuated, recombinant poliovirus (PV), PVSRIPO, because of the naturally evolved tropism of PV for DCs. In humans or chimpanzees, oral PV infection leads to remarkably effective targeting of CD11c+DCs in peripheral (gastrointestinal) and lymphoid tissues. PVSRIPO, engineered with an IRES from human rhinovirus type 2, lacks cytopathogenicity in normal cells, eg. DCs. Rather, DC infection yields ‘sustained’ type-I interferon (IFN) responses elicited by specific viral dsRNA patterns that engage the PV pattern recognition receptor (PRR) MDA5. Mechanistic investigations of PVSRIPO treatment in ex vivo human tumor slices revealed that: (i) the main outcome is sustained type-I IFN release from myeloid cell subsets in the non-malignant TME; (ii) PVSRIPO’s unique innate imprint provides optimal DC activation stimuli for CD4+T cell TH1-polarization and CD8+T cell priming; (iii) PVSRIPO’s ‘PRR-contextualized’ IFN response induces polyfunctional GzmB+, IFNg+, T-bet+ antitumor CD8+T cells that control tumor growth after adoptive transfer. We reported very promising Ph1 clinical trial results with PVSRIPO in challenging indications: recurrent glioblastoma and recurrent, nonresectable melanoma. Our premise is that PVSRIPO therapy recruits cDC1s, leads to local infection of these cells, induces migration to lymph nodes/spleen, and stimulates tumor antigen cross-presentation via the intrinsic innate inflammatory signature it elicits. We propose mechanistic and translational studies to gain insight into targeting of DCs by PVSRIPO, the way sublethal infection of distinct myeloid subsets activates tumor antigen cross-presentation, and rational means of enhancing DC engagement by intranodal virus administration. We propose the following Specific Aims: (1) Unravel mechanisms of cDC1 recruitment, activation, and lymph node migration upon PVSRIPO infection of the TME. (2) Determine the mononuclear phagocyte compartment(s) that mediate PVSRIPO antitumor effects; test the roles of T cell-intrinsic IFN signaling and chemotaxis. (3) Reinforce cDC1 engagement by perinodal delivery or upon infection of the PVSRIPO-reactive glioma myeloid infiltrate. Significance: these studies explore a unique opportunity for effectively engaging CD103+DCs in tumor antigen cross-presentation and CD8+T cell priming, based on the natural tropism for DCs and unique innate inflammatory imprint of PVSRIPO. The long-term objective of this research is to provide means for re-instating effective cancer immune surveillance in patients by overcoming tumor-associated deficits in DC function and CD8+T cell priming.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
