Classical Hodgkin lymphomas (cHLs) are unusual B-cell tumors in which rare malignant Hodgkin Reed Sternberg (HRS) cells are embedded within an extensive, but ineffective, inflammatory/immune cell infiltrate (Figure 1). In earlier studies, we found that cHLs had near-uniform copy gain of 9p24.1/CD274(PD-L1)/PDCD1LG2(PD-L2) – a genetic basis for PD-1 mediated immune evasion¹. The findings were rapidly translated into clinical trials in which patients with cHL had the highest reported response rates to PD-1 blockade^2-4. Despite this clinical success, the mechanism of action of PD-1 blockade in cHL remained undefined.

In certain solid tumors, PD-1 blockade is reported to increase the activity of CD8⁺ cytotoxic T-cells which recognize tumor antigens via MHC class I. However, malignant HRS cells are largely MHC class I-negative, as a consequence of genetic perturbations of B2M or MHC class I gene loci^5,6.

In clinical trials of PD-1 blockade, we previously found that responses were significantly associated with HRS cell expression of MHC class II, but not of MHC class I, suggesting a potential role for CD4⁺ T-cells⁵. Additionally, the cHL immune cell infiltrate was significantly enriched for CD4⁺ T-cells, including in the immediate vicinity of HRS cells^7,8.

In the current study (click here), our collaborative group used the complementary approaches of T-cell receptor (TCR) sequencing and cytometry by time-of-flight (CyTOF) analyses to characterize the peripheral immune signature of patients with cHL who received anti-PD-1 therapy (Figure 2).

PD-1 blockade was most effective in patients with a diverse baseline TCR repertoire and an associated expansion of singleton, rather than non-singleton clones, during therapy. CD4⁺, but not CD8⁺, TCR diversity significantly increased on treatment, most notably in patients who obtained complete responses to PD-1 blockade. In addition, responding patients had increased numbers of circulating activated natural killer cells and a recently identified granzyme B-positive subset. Our studies revealed the roles of newly expanded, clonally diverse, CD4⁺ T-cells and additional innate effectors in the response to PD-1 blockade in cHL.

References

1. Roemer MG, Advani RH, Ligon AH, et al. PD-L1 and PD-L2 Genetic Alterations Define Classical Hodgkin Lymphoma and Predict Outcome. J Clin Oncol. 2016;34(23):2690-2697.
2. Ansell SM, Lesokhin AM, Borrello I, et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma. N Engl J Med. 2015;372(4):311-319.
3. Armand P, Engert A, Younes A, et al. Nivolumab for Relapsed/Refractory Classic Hodgkin Lymphoma After Failure of Autologous Hematopoietic Cell Transplantation: Extended Follow-Up of the Multicohort Single-Arm Phase II CheckMate 205 Trial. J Clin Oncol. 2018;36(14):1428-1439.
4. Chen R, Zinzani PL, Fanale MA, et al. Phase II Study of the Efficacy and Safety of Pembrolizumab for Relapsed/Refractory Classic Hodgkin Lymphoma. J Clin Oncol. 2017;35(19):2125-2132.
5. Roemer MGM, Redd RA, Cader FZ, et al. Major Histocompatibility Complex Class II and Programmed Death Ligand 1 Expression Predict Outcome After Programmed Death 1 Blockade in Classic Hodgkin Lymphoma. J Clin Oncol. 2018;36(10):942-950.
6. Wienand K, Chapuy B, Stewart C, et al. Genomic analyses of flow-sorted Hodgkin Reed-Sternberg cells reveal complementary mechanisms of immune evasion. Blood Adv. 2019;3(23):4065-4080.
7. Cader FZ, Schackmann RCJ, Hu X, et al. Mass cytometry of Hodgkin lymphoma reveals a CD4(+) regulatory T-cell-rich and exhausted T-effector microenvironment. Blood. 2018;132(8):825-836.
8. Carey CD, Gusenleitner D, Lipschitz M, et al. Topological analysis reveals a PD-L1-associated microenvironmental niche for Reed-Sternberg cells in Hodgkin lymphoma. Blood. 2017;130(22):2420-2430.