Tackling the dysregulated immune-checkpoints in classical Hodgkin lymphoma: bidirectional regulations between the microenvironment and Hodgkin/Reed-Sternberg cells

Abstract

Immune evasion is considered one of the modern hallmarks of cancer and is a key element in the pathogenesis of classical Hodgkin Lymphoma (cHL). This haematological cancer achieves effective avoidance of the host's immune system by overexpressing the PD-L1 and PD-L2 proteins on the surface of the neoplastic cells. Subversion of the PD-1/PD-L axis, however, is not the sole contributor to immune evasion in cHL, as the microenvironment nurtured by the Hodgkin/Reed-Sternberg cells is a major player in the creation of a biological niche that sustains their survival and hinders immune recognition. In this review, we will discuss the physiology of the PD-1/PD-L axis and how cHL is able to exploit a plethora of different molecular mechanisms to build an immunosuppressive microenvironment and achieve optimal immune evasion. We will then discuss the success obtained by checkpoint inhibitors (CPI) in treating cHL, both as single agents and as part of combination strategies, analysing the rationale for their combination with traditional chemotherapeutic compounds and the proposed mechanisms of resistance to CPI immunotherapy.

Keywords: Hodgkin lymphoma; LAG-3; PD-1; Treg; immune checkpoint inhibitors; microenvironment; nivolumab; pembrolizumab.

Figure 1

Phyisiology of the PD-1/PD-L1 axis and main pathways of immune modulation in cHL. After binding to PD-L1/PD-L2, PD-1 undergoes autophosphorylation on its ITSM and ITIM, recruiting and activating SHP2. This phosphatase acts as the main effector, truncating the TCR activation signals by inhibiting ZAP70, LCK and the TCRζ subunit. The inhibition of the PI3K/Akt pathway also stops the T-cell from switching its metabolism from fatty acid oxidation to glycolysis, glutaminolysis and the utilisation of BCAA, which is a core element of T-cell activation. SHP2 also inhibits the PI3K/Akt pathway by directly interfering with the PI3K activity and by inhibiting the kinase CK2, thus allowing PTEN to dephosphorylate PIP3. Moreover, SHP2 directly inhibits PLCγ1 thus hindering the production of IP3 and DAG and the activation of PKC and the Ras/MEK/ERK pathway. DAG, Diacylglycerol; IP3, Inositol triphosphate; PKC, Protein kinase C.

Figure 2

Main pathways of immune modulation in cHL. HRSC avoid immune detection with several different mechanisms. The overexpression of PD-L1 and CD86 allows for interaction and inhibition with two different subsets of T-lymphocytes (PD-1+ and PD-1-/CTLA-4+, respectively). Frequent mutations in the β2M gene hinder antigen presentation to T-cells by producing a defective MHC-I receptor, whose interactions are replaced by the inhibitory HLA-G receptor. Moreover, the MHC-II receptor expressed by HRSC is able to bind the inhibitory LAG-3 receptor expressed on exhausted T-cells in the microenvironment further downregulating their activity. The overexpression of FAS-L induces apoptosis in lymphocytes bearing the FAS receptor. The presence of the IDO enzyme, produced both by HRSC and microenvironment cells, causes Trp depletion, which forces a regulatory differentiation of T-cells, and Kynurenine accumulation, which induces T-cell death. The expression of Gal1 on the surface of HRSC further increases the recruitment of Treg to the microenvironment. Kyn, Kynurenine; Trp, Tryptophan.

Figure 3

Histological and Immunohistochemical features of cHL’s microenvironment. Scattered HRSCs are embedded in a reactive microenvironment (ME). CD4+ PD-1+ lymphocytes are enriched around HRSCs, often organised in rosettes. Numerous CD163+ M2 macrophages are also present, while CD8+ T lymphocytes and CD20+ B lymphocytes are sparse. (H&E and immunoperoxidase stains; original magnification 63x).

Figure 4

Immune-checkpoint inhibitors in cHL. Nivo and Pembro are the only approved CPIs for cHL. They act mainly by binding PD-1+ T-helper lymphocytes in the tumour microenvironment, thus reducing the inhibitory effect of PD-L1 overexpression on HRSC and restoring T-cell mediated anti-tumour immunity. They also reduce the interactions between PD-1+ T-helper lymphocytes and PD-L1+ TAMs, allowing T-helper lymphocytes to closely interact with HRSC without the inhibitory influence of TAMs. Moreover, Nivo has been shown to be able to directly reduce PD-L1 expression on TAMs through mechanisms which are still being investigated. Favelizumab (Fav) is a LAG-3 directed monoclonal antibody currently being tested in combination with anti-PD-1 CPIs within clinical trials, acting as an inhibitor of the LAG-3/MHC-II interaction, thus impinging Treg function and freeing up MHC-II molecules for CD4/MHC-II interactions on activated T-helper lymphocytes. Camidanlumab-Teserine (Cami) is a CD25 directed drug-antibody conjugate that acts by directly binding to IL-2Rα (CD25) on the surface of HRSC and delivering its toxic payload directly to neoplastic cells. As CD25 is also expressed on the surface of Tregs, the activity of Cami might be partially due to Treg depletion and subsequent restoration of competent anti-tumour immunity. TAM, Tumour-associated macrophage.