PD-1 Blockade Reinvigorates Bone Marrow CD8+ T Cells from Patients with Multiple Myeloma in the Presence of TGFβ Inhibitors

Abstract

Purpose: Immune-checkpoint inhibitors have shown therapeutic efficacy in various malignant diseases. However, antiprogrammed death (PD)-1 therapy has not shown clinical efficacy in multiple myeloma.Experimental Design: Bone marrow (BM) mononuclear cells were obtained from 77 newly diagnosed multiple myeloma patients. We examined the expression of immune-checkpoint receptors in BM CD8 þ T cells and their functional restoration by ex vivo treatment with anti-PD-1 and TGFb inhibitors.Results: We confirmed the upregulation of PD-1 and PD-L1 expression in CD8 þ T cells and myeloma cells, respectively, from the BM of multiple myeloma patients. PD-1-expressing CD8 þ T cells from the BM of multiple myeloma patients coexpressed other checkpoint inhibitory receptors and exhibited a terminally dif-ferentiated phenotype. These results were also observed in BM CD8 þ T cells specific to myeloma antigens NY-ESO-1 and HM1.24. BM CD8 þ T cells from multiple myeloma patients exhibited reduced proliferation and cytokine production upon T-cell receptor stimulation. However, anti-PD-1 did not increase the proliferation of BM CD8 þ T cells from multiple myeloma patients, indicating that T-cell exhaustion in multiple myeloma is hardly reversed by PD-1 blockade alone. Intriguingly, anti-PD-1 significantly increased the proliferation of BM CD8 þ T cells from multiple myeloma patients in the presence of inhibitors of TGFb, which was overexpressed by myeloma cells.Conclusions: Our findings indicate that combined blockade of PD-1 and TGFb may be useful for the treatment of multiple myeloma.

Understanding the Immune-Stroma Microenvironment in B Cell Malignancies for Effective Immunotherapy

“…In addition, cancer-associated stroma can be efficiently targeted to boost anti-tumor immunity, and fibroblasts-specific pharmacological approaches (anti-FAP antibodies or CAR-T) have been shown to induce tumor regression (284). Tumor stroma can also be 'normalized' by blocking or neutralizing cancer-secreted factors that promote stromal cell activation (Endostatin, Imatinib, anti-TGFb) (285)(286)(287). Moreover, the presence of cancer-stroma-specific proteins can be used to activate tissue resident anti-tumor T cells using stromaspecific/T cells co-stimulatory fusion proteins (FAP-4-1BBL) (282).…”

“…As described above, TGF β , TNFα and LT are all master regulators of immunosuppressive fibroblast function in hematological malignancies, and the use of neutralizing antibodies against these molecules could provide an interesting approach for stroma normalization, as already demonstrated in solid tumors ( 294 ). Combined blockade of TGF β and anti-PD-1 in MM has been shown to promote anti-tumor T cell activation and proliferation, indicating that targeting the different immunosuppressive pathways occurring in the TME can reactivate endogenous anti-tumor immune responses and favor tumor clearance ( 287 ).…”

Metastatic cutaneous squamous cell carcinoma responsive to cemiplimab in a patient with multiple myeloma

“…Despite the effectiveness of PD-1 inhibitors against several types of solid cancers, including cSCC, the utility of this drug class against hematologic neoplasms is less clear (except for treatment of classic Hodgkin lymphoma). 4 , 5 , 6 , 7 , 8 , 9 Although our patient had a clinical response of cSCC to cemiplimab, he did experience eventual progression of his MM with increase in M spike 11 months after starting PD-1 inhibition, necessitating addition of carfilzomib to his MM treatment regimen.…”

PD-L1/PD-1 Axis in Multiple Myeloma Microenvironment and a Possible Link with CD38-Mediated Immune-Suppression

“…Conversely, Paiva et al [ 40 ] showed no differences among MM, MGUS and HDs on both T cells and NK cells; while a significant increase in PD-1 expression on both CD4+ and CD8+ cells was detected in MRD+ and RMM patients as compared with NDMM. In contrast with these results, a study from Kwon M et al [ 56 ] compared %CD8+PD-1+ cells between MGUS/SMM and NDMM which displayed a higher % as compared with the other group. In addition, PD-1 expression has been described on the anergic BM Vg9Vd2 T cell subset from MGUS patients and remained upregulated in MM after clinical remission [ 50 ].…”