Cancer-specific innate and adaptive immune rewiring drives resistance to PD-1 blockade in classic Hodgkin lymphoma

Julia Paczkowska, Ming Tang, Kyle T. Wright, Li Song, Kelsey Luu, Vignesh Shanmugam, Emma L. Welsh, Jason L. Weirather, Naomi Besson, Harrison Olszewski, Billie A. Porter, Kathleen L. Pfaff, Robert A. Redd, Fathima Zumla Cader, Elisa Mandato, Jing Ouyang, Eleonora Calabretta, Gali Bai, Lee N. Lawton, Philippe Armand, Scott J. Rodig, Xiaole Shirley Liu and Margaret A. Shipp ()
Additional contact information
Julia Paczkowska: Dana-Farber Cancer Institute
Ming Tang: Dana-Farber Cancer Institute
Kyle T. Wright: Brigham and Women’s Hospital
Li Song: Dana-Farber Cancer Institute
Kelsey Luu: Dana-Farber Cancer Institute
Vignesh Shanmugam: Brigham and Women’s Hospital
Emma L. Welsh: Brigham and Women’s Hospital
Jason L. Weirather: Dana-Farber Cancer Institute
Naomi Besson: Brigham and Women’s Hospital
Harrison Olszewski: Brigham and Women’s Hospital
Billie A. Porter: Brigham and Women’s Hospital
Kathleen L. Pfaff: Brigham and Women’s Hospital
Robert A. Redd: Dana-Farber Cancer Institute
Fathima Zumla Cader: Dana-Farber Cancer Institute
Elisa Mandato: Dana-Farber Cancer Institute
Jing Ouyang: Dana-Farber Cancer Institute
Eleonora Calabretta: Dana-Farber Cancer Institute
Gali Bai: Dana-Farber Cancer Institute
Lee N. Lawton: Dana-Farber Cancer Institute
Philippe Armand: Dana-Farber Cancer Institute
Scott J. Rodig: Brigham and Women’s Hospital
Xiaole Shirley Liu: Dana-Farber Cancer Institute
Margaret A. Shipp: Dana-Farber Cancer Institute

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: Abstract Hodgkin Reed-Sternberg (HRS) cells of classic Hodgkin lymphoma (cHL), like many solid tumors, elicit ineffective immune responses. However, patients with cHL are highly responsive to PD-1 blockade, which largely depends on HRS cell-specific retention of MHC class II and implicates CD4+ T cells and additional MHC class I-independent immune effectors. Here, we utilize single-cell RNA sequencing and spatial analysis to define shared circulating and microenvironmental features of the immune response to PD-1 blockade in cHL. Compared with non-responders, responding patients have more circulating CD4+ naïve and central memory T cells and B cells, as well as more diverse CD4+ T cell and B cell receptor repertoires. Importantly, a population of circulating and tumor-infiltrating IL1β+ monocytes/macrophages is detectable in patients with cHL but not healthy donors, and a proinflammatory, tumor-promoting signature of these circulating IL1β+ monocytes is associated with resistance to PD-1 blockade in cHL. Altogether, our findings reveal extensive immune rewiring and complementary roles of CD4+ T cells, B cells and IL1β+ monocytes in the response to PD-1 blockade and suggest that these features can be captured with a peripheral blood test.

Date: 2024
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DOI: 10.1038/s41467-024-54512-7

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