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BTLA+CD200+ B cells dictate the divergent immune landscape and immunotherapeutic resistance in metastatic vs. primary pancreatic cancer

Abstract

Response to cancer immunotherapy in primary versus metastatic disease has not been well-studied. We found primary pancreatic ductal adenocarcinoma (PDA) is responsive to diverse immunotherapies whereas liver metastases are resistant. We discovered divergent immune landscapes in each compartment. Compared to primary tumor, liver metastases in both mice and humans are infiltrated by highly anergic T cells and MHCIIloIL10+ macrophages that are unable to present tumor-antigen. Moreover, a distinctive population of CD24+CD44CD40 B cells dominate liver metastases. These B cells are recruited to the metastatic milieu by Muc1hiIL18hi tumor cells, which are enriched >10-fold in liver metastases. Recruited B cells drive macrophage-mediated adaptive immune-tolerance via CD200 and BTLA. Depleting B cells or targeting CD200/BTLA enhanced macrophage and T-cell immunogenicity and enabled immunotherapeutic efficacy of liver metastases. Our data detail the mechanistic underpinnings for compartment-specific immunotherapy-responsiveness and suggest that primary PDA models are poor surrogates for evaluating immunity in advanced disease.

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Fig. 1: Primary PDA is responsive to PD-L1-targeted immunotherapy whereas liver metastases are resistant.
Fig. 2: Divergent immune landscape in primary versus metastatic PDA.
Fig. 3: T cells infiltrating PDA liver metastases are less immunogenic than in primary tumor.
Fig. 4: TAMs have reduced capacity for antigen presentation in metastatic PDA compared to primary tumor.
Fig. 5: Distinct B-cell profiles in primary and metastatic PDA.
Fig. 6: B cells corrupt innate and adaptive immunity in PDA liver metastases.
Fig. 7: Targeting B cells, CD200, or BTLA in PDA liver metastases enables efficacy for checkpoint-based immunotherapy.

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Funding

This work was supported by the American College of Surgeons Resident Research Fellowship (BD), Deutsche Forschungsgemeinschaft grant AY 126/1-1 (BA), and NIH grants CA168611 (DC, GM), CA203105 (GM), CA215471 (GM), CA19311 (GM), and DK106025 (GM).

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BD and SA prepared the paper, performed in vivo and in vitro experiments and data analysis, and designed, supervised and interpreted the study; GSS, ML, BS, EL, MSS, AF, FY, CH, JG, AP, and YW performed in vitro experiments; JL, RC, RDS, MFC, CB, WW, SAAS, and GW performed in vivo experiments in addition to paper and figure preparation; BA and MK performed data analyis; DC contributed to critical review and paper writing; GM conceived, designed, supervised, analyzed and interpreted the study and provided critical review, and is senior author and corresponding author.

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Correspondence to George Miller.

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Diskin, B., Adam, S., Soto, G.S. et al. BTLA+CD200+ B cells dictate the divergent immune landscape and immunotherapeutic resistance in metastatic vs. primary pancreatic cancer. Oncogene 41, 4349–4360 (2022). https://doi.org/10.1038/s41388-022-02425-4

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