The Cellular and Architectural Determinants of Immune Evasion and Their Impact on Response to Therapy in Classical Hodgkin Lymphoma


IN PARTNERSHIP WITH LEUKEMIA & LYMPHOMA SOCIETY AND THE PAUL G. ALLEN FRONTIERS GROUP (2020-PRESENT)

Margaret A. Shipp, MD, Dana-Farber Cancer Institute/ Harvard Medical School

Immune checkpoint blockade therapy targeting PD-1/PD-L1 has transformed the treatment and prognosis for many cancer patients. Notably, it has seen successes in managing relapsed or refractory classical Hodgkin’s lymphoma, which expresses high levels of PD-L1. However, despite initial response to such therapy, most patients will eventually relapse. Thus, despite high levels of PD-L1 expression, there is an incomplete understanding of how these lymphomas come to resist PD-1/PD-L1 checkpoint blockade, mostly likely the result of multiple pathways capable of promoting immune evasion.

To address these questions, Margaret Shipp and her collaborators are using a novel technique to probe the immune microenvironment in Hodgkin’s lymphoma. They are employing multiplex ion beam imaging time of flight mass spectrometry (MIBI-TOF), which uses antibodies conjugated to rare metal isotopes to understand the spatial organization of immune and tumor markers. MIBI-TOF allows for more precision than fluorescent markers, which can be difficult to deconvolute because of spectral overlap. They are harnessing this unprecedented spatial resolution to observe the immune response in the native tumor microenvironment in samples from patients who have been treated with induction therapy or PD-1 blockade. Finally, they will further characterize cells in the tumor microenvironment by single cell RNA sequencing, which when combined with MIBI-TOF data, will identify novel vulnerabilities of these cells and other rational therapeutic targets. These studies will provide insight into the complex immune evasion strategies used by tumors and set the foundation for novel therapies to augment treatments.

PUBLISHED RESEARCH

Griffin GK, Weirather JL, Roemer MGM, Lipschitz M, Kelley A, Chen PH, Gusenleitner D, Jeter E, Pak C, Gjini E, Chapuy B, Rosenthal MH, Xu J, Chen BJ, Sohani AR, Lovitch SB, Abramson JS, Ishizuka JJ, Kim AI, Jacobson CA, LaCasce AS, Fletcher CD, Neuberg D, Freeman GJ, Hodi FS, Wright K, Ligon AH, Jacobsen ED, Armand P, Shipp MA, Rodig SJ. Spatial signatures identify immune escape via PD-1 as a defining feature of T-cell/histiocyte-rich large B-cell lymphoma. Blood. 2021.

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