A bilateral tumor model identifies transcriptional programs associated with patient response to immune checkpoint blockade

Abstract

Immune checkpoint blockade (ICB) is efficacious in many diverse cancer types, but not all patients respond. It is important to understand the mechanisms driving resistance to these treatments and to identify predictive biomarkers of response to provide best treatment options for all patients. Here we introduce a resection and response-assessment approach for studying the tumor microenvironment before or shortly after treatment initiation to identify predictive biomarkers differentiating responders from nonresponders. Our approach builds on a bilateral tumor implantation technique in a murine metastatic breast cancer model (E0771) coupled with anti-PD-1 therapy. Using our model, we show that tumors from mice responding to ICB therapy had significantly higher CD8+ T cells and fewer Gr1+CD11b+ myeloid-derived suppressor cells (MDSCs) at early time points following therapy initiation. RNA sequencing on the intratumoral CD8+ T cells identified the presence of T cell exhaustion pathways in nonresponding tumors and T cell activation in responding tumors. Strikingly, we showed that our derived response and resistance signatures significantly segregate patients by survival and associate with patient response to ICB. Furthermore, we identified decreased expression of CXCR3 in nonresponding mice and showed that tumors grown in Cxcr3−/− mice had an elevated resistance rate to anti-PD-1 treatment. Our findings suggest that the resection and response tumor model can be used to identify response and resistance biomarkers to ICB therapy and guide the use of combination therapy to further boost the antitumor efficacy of ICB.

Temporally restricted activation of IFNβ signaling determines response to immune checkpoint therapy

“…We have previously used these bilateral models to identify transcriptomic ICB response signatures in the early tumor microenvironment and extensively validated our ndings in separate patient cohorts of bladder cancer and melanoma patients treated with ICB 6,16 . In addition, our results using these models have been independently validated by other research groups in preclinical models and patient cohorts with various tumor types, underscoring their translational relevance [17][18][19][20] . Here, we aimed to discover time-critical events in the tumor microenvironment that underlie ICB e cacy.…”

ICAM-1 orchestrates the abscopal effect of tumor radiotherapy

“…1 A and B). BALB/c mice were inoculated with a primary tumor (irradiated tumor) and a secondary tumor (nonirradiated tumor) to mimic the primary tumor and metastatic lesions in a clinical scenario (19,20). Because RT alone rarely induces an abscopal effect in preclinical or clinical studies (2, 21), we artificially defined "responsive" and "nonresponsive" by a relatively low criterion to better explore biomarkers in the early treatment stage.…”

CD8+ T Cell Exhaustion in Cancer

“…Emergent data suggest that the CCR5 and CXCR3 chemokine receptor pathways are needed for anti-PD-(L)1-mediated CD8 + T ex tumor recruitment and/or intratumoral positioning (101)(102)(103)(104). Heightened dual expression of the ligands for CCR5 and CXCR3 (CCL5 and CXCL9, respectively) positively correlates with the amount of tumor CD8a transcripts and patient survival in cancers of the ovary, breast, lung, colon, as well as melanoma (103).…”