Immunogenic chemotherapy sensitizes tumors to checkpoint blockade therapy

By C. Pfirschke, Camilla Engblom, S. Rickelt, V. Cortez-Retamozo, Christopher S. Garris, F. Pucci, T. Yamazaki, Vichnou Poirier Colame, Andita Newton, Younes Redouane and 11 more. Immunity, 2016

893 citations recorded by the source corpus.

SUMMARY Checkpoint blockade immunotherapies can be extraordinarily effective, but may benefit only the minority of patients whose tumors are pre-infiltrated by T cells. Here, using lung adenocarcinoma mouse models, including genetic models, we show that autochthonous tumors that lacked T cell infiltration and resisted current treatment options could be successfully sensitized to host antitumor T cell immunity when using appropriately selected immunogenic drugs (e.g. oxaliplatin combined with cyclophosphamide for treatment against tumors expressing oncogenic Kras and lacking Trp53). The antitumor response was triggered by direct drug actions on tumor cells, relied on innate immune sensing through toll-like receptor 4 signaling, and ultimately depended on CD8+ T cell antitumor immunity. Furthermore, instigating tumor infiltration by T cells sensitized tumors to checkpoint inhibition and controlled cancer durably. These findings indicate that the proportion of cancers responding to checkpoint therapy can be feasibly and substantially expanded by combining checkpoint blockade with immunogenic drugs.

Subfields: Immunology, Oncology

View Paper: https://www.semanticscholar.org/paper/26419a4d41df24bd7ff84924e21550e8033cebac

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In Immunology

1. Alycia Gardner
2. M. Pittet
3. Daniel G. Tenen
4. B. Ruffell

In Oncology

1. M. Pittet
2. B. Ruffell

Citations in the corpus

• Single cell transcriptomics of human and mouse lung cancers reveals conserved myeloid populations across individuals and species (2019, methodology): “Tumor burden was scored by measuring postmortem lung weight as proxy for tumor burden as previously described (Pfirschke et al., 2016).”
• Resistance Mechanisms to Immune-Checkpoint Blockade in Cancer: Tumor-Intrinsic and -Extrinsic Factors. (2016, neutral): “…administration of appropriately selected chemotherapies ahead of ICB therapy, capable of transforming tumors into better immunological areas with significant T cell infiltration (i.e., restoring a high Teff-Treg ratio), improves ICB-mediated inhibition of tumor progression (Pfirschke et al., 2016).”
• Dendritic Cells and Cancer Immunity (2016, background): “Despite this knowledge gap, HMGB1 expression is the most distinguishing characteristic of immunogenic cell death, as ATP release occurs under many conditions of cellular stress [34, 41].”