Cancer-specific innate and adaptive immune rewiring drives resistance to PD-1 blockade in classic Hodgkin lymphoma
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<sup>+</sup> 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<sup>+</sup> naïve and central memory T cells and B cells, as well as more diverse CD4<sup>+</sup> T cell and B cell receptor repertoires. Importantly, a population of circulating and tumor-infiltrating IL1β<sup>+</sup> monocytes/macrophages is detectable in patients with cHL but not healthy donors, and a proinflammatory, tumor-promoting signature of these circulating IL1β<sup>+</sup> monocytes is associated with resistance to PD-1 blockade in cHL. Altogether, our findings reveal extensive immune rewiring and complementary roles of CD4<sup>+</sup> T cells, B cells and IL1β<sup>+</sup> monocytes in the response to PD-1 blockade and suggest that these features can be captured with a peripheral blood test.
Authors
- Emma L. Welsh (ORCID: https://orcid.org/0009-0009-7345-5106)
- Li Song
- Robert Allyn Redd (ORCID: https://orcid.org/0000-0002-1329-5288)
- Jason L. Weirather (ORCID: https://orcid.org/0000-0003-0556-0616)
- Eleonora Calabretta (ORCID: https://orcid.org/0000-0002-8105-1322)
- Margaret A. Shipp (ORCID: https://orcid.org/0000-0002-3949-6897)
- Gali Bai (ORCID: https://orcid.org/0000-0003-4488-5499)
- Jing Ouyang (ORCID: https://orcid.org/0000-0001-5902-7070)
- Lee N. Lawton (ORCID: https://orcid.org/0000-0001-7824-9787)
- Vignesh Shanmugam (ORCID: https://orcid.org/0000-0002-2005-9080)
- N. Besson (ORCID: https://orcid.org/0009-0008-3548-913X)
- X. Shirley Liu (ORCID: https://orcid.org/0000-0003-4736-7339)
- Philippe A. Armand (ORCID: https://orcid.org/0000-0001-6098-1603)
- Kyle Wright (ORCID: https://orcid.org/0000-0003-2816-0260)
- Fathima Zumla Cader (ORCID: https://orcid.org/0000-0001-5107-0146)
- Scott J. Rodig (ORCID: https://orcid.org/0000-0003-1761-9769)
- Kelsey Luu (ORCID: https://orcid.org/0000-0002-1186-0538)
- Julia Paczkowska (ORCID: https://orcid.org/0000-0002-3976-4353)
- Elisa Mandato (ORCID: https://orcid.org/0000-0002-7443-2821)
- Kathleen L. Pfaff (ORCID: https://orcid.org/0000-0003-3311-5384)
- Ming Tang
- Billie Porter
- Harrison Olszewski
Institutions
- AstraZeneca (United Kingdom) (GB)
- Broad Institute (US)
- Dartmouth College (US)
- Brigham and Women's Hospital (US)
- Harvard University (US)
- University of California, Santa Cruz (US)
- Critical Path Institute (US)
- Bristol-Myers Squibb (United States) (US)
- Dana-Farber Cancer Institute (US)
- PathAI (United States) (US)
- G1 Therapeutics (United States) (US)
- AstraZeneca (United States) (US)
- University of Oklahoma Health Sciences Center (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-12-30
- DOI
- https://doi.org/10.1038/s41467-024-54512-7
- Citations
- 9
- Primary Topic
- Immune Cell Function and Interaction
- Type
- article
- Field-Weighted Citation Impact
- 2.16
Funders
- Bristol-Myers Squibb
- Associazione Italiana per la Ricerca sul Cancro