In chronic infections or cancer, stimulated CD8+ T cells progress along a trajectory towards terminal exhaustion in sites of antigen abundance. However, how these cells respond when antigen recognition is lost has not been concretely elucidated.
The Masopust lab generated a UBC-CreERT2 x P14 fl/fl mouse model that allows for the inducible excision of P14 TCR to precisely answer these questions, which has been used successfully in the setting of acute and chronic infections (unpublished work). Here, we combined this mouse model with the KP-NINJA tumor model (Fitzgerald et. al., 2021) that develop autochthonous lung tumors that progress slowly and express the gp33/H-2Db epitope that is recognized by the P14 TCR.
Preliminary results showed successful infiltration and activation of these transgenic T cells in the KP-NINJA tumor microenvironment as well as accumulation within the tumor-draining lymph node following adoptive transfer. After three weeks of antigen exposure, the TCR was eliminated from 50% of transferred T cells and flow cytometry of the tumor, tumor-draining lymph node and additional tissues was performed one-week post-excision. TCR-negative T cells persisted within solid tumors and draining lymph node, although their phenotype was distinct from co-transferred TCR-positive P14 T cells. TCR-negative cells had decreased PD-1 and TOX expression in the tumor and tumor-draining lymph node and increased CXCR6 and CD127 expression within these tissues.
Ongoing studies will define tumor-specific T cell differentiation and fate after TCR excision, investigate changes to cell localization, and test functional potential. This work will add to our understanding of the development of T cell exhaustion and the plasticity of lineage commitment in cancer to better inform future anti-cancer therapeutics.
n/a
Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)
Matthew B. Watowich, Jenny Krause, O. Smith et al.· Journal of Immunology· 0 citations
Solid tumors are populated with functional, non-circulating virus-specific CD8+ T cells, primed for rapid response to re-infection. Immunosurveillance by these memory T cells is evident across multiple tissues and solid tumors. Activation of these bystander cells triggers clearance of poorly immunogenic tumors in mice and is phenocopied in human tumor explants through unknown mechanisms — putatively involving the adjuvanting of tumor-specific T cell responses — providing the basis for a Phase I immunotherapy trial termed peptide alarm therapy (PAT).
To define mechanisms of PAT mediated tumor clearance in murine models, we used single-cell multi-omics, targeted immune cell depletions, and genetic manipulations. We mapped how viral peptides influence antiviral T cell states and by what axes they signal to activate the innate and adaptive immune system to mount an effective response against malignant cells. We validated our multi-omic approach via in vivo studies to measure treatment efficacy in the context of key immune cell depletion and pathway inhibitions.
We initially hypothesized that tumors were cleared in an antigen-specific manner; however, PAT cured without conventional recognition-dependent mechanisms and in the absence of any tumor-specific TCRab T cell. Mechanistically, robust T cell activation recruited immune cells, utilized innate leukocytes, and triggered a tumoricidal combination of effector molecules and panoptotic pathways, resulting in tumor-specific clearance independent of conventional T cell mechanisms. IFN-γ, TNF, and NO induced caspase-dependent death, recapitulating melanoma cures in mice or human melanoma cell death in vitro. Gene expression signatures of immune and tumor cell types involved in this panoptotic pathway were predictive of survival among human melanoma patients.
Thus, triggering productive T cell activation within tumors can be sufficient for immunotherapy, without needing to induce or rescue cancer-specific responses.
F30CA253992, R01CA238439, DP1238659
Computational and Systems Immunology (COMP)
Tyler Dao, Noah V. Gavil, M. Geller et al.· Journal of Immunology· 0 citations
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