AI Article Synopsis

  • Despite good responses to PD-1 blockade in cancer treatment, many patients do not respond, similar to observations in the CT26 tumor mouse model, where most tumors remained unaffected by anti-PD-1 therapy.
  • The study found that injecting a TLR9 agonist, SD-101, directly into tumors that did not respond to anti-PD-1 resulted in complete rejection of injected tumors and some distant ones, significantly increasing T-cell infiltration and IFN expression.
  • The combination treatment improved the number and quality of CD8 T cells, enhancing immune response against tumors and suggesting that adding intratumoral SD-101 might help boost the effectiveness of PD-1 blockade in cancer patients.

Article Abstract

Despite the impressive rates of clinical response to programmed death 1 (PD-1) blockade in multiple cancers, the majority of patients still fail to respond to this therapy. The CT26 tumor in mice showed similar heterogeneity, with most tumors unaffected by anti-PD-1. As in humans, response of CT26 to anti-PD-1 correlated with increased T- and B-cell infiltration and IFN expression. We show that intratumoral injection of a highly interferogenic TLR9 agonist, SD-101, in anti-PD-1 nonresponders led to a complete, durable rejection of essentially all injected tumors and a majority of uninjected, distant-site tumors. Therapeutic efficacy of the combination was also observed with the TSA mammary adenocarcinoma and MCA38 colon carcinoma tumor models that show little response to PD-1 blockade alone. Intratumoral SD-101 substantially increased leukocyte infiltration and IFN-regulated gene expression, and its activity was dependent on CD8 T cells and type I IFN signaling. Anti-PD-1 plus intratumoral SD-101 promoted infiltration of activated, proliferating CD8 T cells and led to a synergistic increase in total and tumor antigen-specific CD8 T cells expressing both IFN-γ and TNF-α. Additionally, PD-1 blockade could alter the CpG-mediated differentiation of tumor-specific CD8 T cells into CD127KLRG1 short-lived effector cells, preferentially expanding the CD127KLRG1 long-lived memory precursors. Tumor control and intratumoral T-cell proliferation in response to the combined treatment is independent of T-cell trafficking from secondary lymphoid organs. These findings suggest that a CpG oligonucleotide given intratumorally may increase the response of cancer patients to PD-1 blockade, increasing the quantity and the quality of tumor-specific CD8 T cells.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5135381PMC
http://dx.doi.org/10.1073/pnas.1608555113DOI Listing

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