Tumor-infiltrating HLA-matched CD4⁺T cells retargeted against Hodgkin and Reed–Sternberg cells

Abstract

Hodgkin lymphoma (HL) presents with a unique histologic pattern. Pathognomonic Hodgkin and Reed-Sternberg (HRS) cells usually account for less than 1% of the tumor and are embedded in a reactive infiltrate mainly comprised of CD4(+) T cells. HRS cells induce an immunosuppressive microenvironment and thereby escape antitumor immunity. To investigate the impact of interactions between HRS cells and T cells, we performed long-term co-culture studies that were further translated into a xenograft model. Surprisingly, we revealed a strong antitumor potential of allogeneic CD4(+) T cells against HL cell lines. HRS and CD4(+) T cells interact by adhesion complexes similar to immunological synapses. Tumor-cell killing was likely based on the recognition of allogeneic major histocompatibility complex class II (MHC-II) receptor, while CD4(+) T cells from MHC-II compatible donors did not develop any antitumor potential in case of HL cell line L428. However, gene expression profiling (GEP) of co-cultured HRS cells as well as tumor infiltration of matched CD4(+) T cells indicated cellular interactions. Moreover, matched CD4(+) T cells could be activated to kill CD30(+) HRS cells when redirected with a CD30-specific chimeric antigen receptor. Our work gives novel insights into the crosstalk between HRS and CD4(+) T cells, suggesting the latter as potent effector cells in the adoptive cell therapy of HL.

Lymphocyte predominant cells of nodular lymphocyte predominant Hodgkin lymphoma interact with rosetting T cells in an immunological synapse

“…Both the possibility of antigen presentation from Hodgkin-Reed-Sternberg cells to the T cells, 27,28 as well as a host-anti-lymphoma response have been discussed. [29][30][31] When T FH markers such as PD1 became available, it became clear that the rosetting T cells in NLPHL and the lymphocyterich classic HL differ from the other subtypes of HL, as they represent T FH cells. 11 In the present study, we confirmed the presence of PD1 + rosetting T cells at similar frequencies in both typical and variant growth pattern NLPHL, and additionally observed that these T cells frequently express CD69.…”

Complex Immune Evasion Strategies in Classical Hodgkin Lymphoma

“…However, an anti-HRS cell activity of CD4 þ T cells against HL cell lines in coculture becomes detectable only after about 6 days of culture (34). Gene expression profiling revealed that after 7 days of coculture with the cHL cell line L428, HLAmatched and -unmatched CD4 þ T cells showed similar changes in their gene expression (34). Hence, the influence of HRS cells on cocultured CD4 þ T cells is stronger than effects through a mismatched MHC class II.…”

“…As CD4 þ T cells were not HLA matched, a potential influence of HLA mismatching on the behavior of the CD4 þ T cells must be considered. However, an anti-HRS cell activity of CD4 þ T cells against HL cell lines in coculture becomes detectable only after about 6 days of culture (34). Gene expression profiling revealed that after 7 days of coculture with the cHL cell line L428, HLAmatched and -unmatched CD4 þ T cells showed similar changes in their gene expression (34).…”

CD30-targeted oncolytic viruses as novel therapeutic approach against classical Hodgkin lymphoma

“…They display three independent patient cases, as they were derived from pleural effusions (KM-H2, L-428) or peripheral blood (L-1236), and cover two different subtypes of HL, namely nodular sclerosis (L-428) and mixed cellularity (KM-H2, L-1236). A preclinical model reflecting the low abundance of tumor cells within the affected tissue is therefore so far not available [ 29 , 30 ]. Hence, we have assessed VSV-CD30 in a mouse model of disseminated growing cHL tumor cells and found a substantial reduction in tumor growth at least for some of the mice.…”

“…Envelope modification as done here, however, has often resulted in attenuation of VSV [ 34 ]. Upon completion, VSV-CD30 will add to a growing list of CD30-targeted therapeutics that include besides antibodies also CD30-specific AAV vectors [ 35 ] and CAR T cells [ 30 , 36 ]. Combining VSV-CD30 with these or other cancer therapeutics such as checkpoint inhibitors will be another future option to be explored.…”