Experimental and clinical evidence in favour of an effective immune stimulation in ER-positive, endocrine-dependent metastatic breast cancer

Abstract

In ER+ breast cancer, usually seen as the low immunogenic type, the main mechanisms favouring the immune response or tumour growth and immune evasion in the tumour microenvironment (TME) have been examined. The principal implications of targeting the oestrogen-mediated pathways were also considered. Recent experimental findings point out that anti-oestrogens contribute to the reversion of the immunosuppressive TME. Moreover, some preliminary clinical data with the hormone-immunotherapy association in a metastatic setting support the notion that the reversion of immune suppression in TME is likely favoured by the G0-G1 state induced by anti-oestrogens. Following immune stimulation, the reverted immune suppression allows the boosting of the effector cells of the innate and adaptive immune response. This suggests that ER+ breast cancer is a molecular subtype where a successful active immune manipulation can be attained. If this is confirmed by a prospective multicentre trial, which is expected in light of the provided evidence, the proposed hormone immunotherapy can also be tested in the adjuvant setting. Furthermore, the different rationale suggests a synergistic activity of our proposed immunotherapy with the currently recommended regimen consisting of antioestrogens combined with cyclin kinase inhibitors. Overall, this lays the foundation for a shift in clinical practice within this most prevalent molecular subtype of breast cancer.

Keywords: ER+ advanced breast cancer; TILs; anti-tumour immune response; cancer-immunity cycle; cyclin kinase 4/6 inhibitors; cytokines; immunotherapy.

Figure 1

Chronic inflammation and high E2 are two mainstays in the TME: proposed mechanisms governing the immune balance. (A) in the absence of antiestrogens (anti-E2), the E2 pathway favors a tumor- promoting immunosuppressive TME shifting the balance in favor of Th2 responses and M2 TAM infiltration compared to Thl responses and M1 TAM infiltration with promotion of the associated cytokines (IL-1, IL-4, IL-6, IL-8, IL-10, IL-17A) and suppressive mediators (TGFbeta, TNFalpha, NFKB, COX2, PGE2). E2 further contributes to immunosuppression through proliferation of Tregs, expansion of MDSCs, induced inhibitory activity of APCs, increased tumor cell PD-L1 expression and inhibition of CD8+ T cell and NK cell induced apoptosis. TME inflammation is sustained by the co-inflammatory cytokines (IL-1, IL-4, IL-6, TNFalpha, NFKB). (B) anti E2 counteracts the immunosuppressive E2 actions (also see Table 1B ); this shifts the balance by increasing the immune response and decreasing the immunosuppression. Immunosuppression is inclusive of immune evasion and immune inhibition; therefore, in ER positive breast cancer in clinical benefit during anti-estrogens, the tumor-promoting immunosuppressive TME is reverted |↔| (C) the addition of the INFbeta- IL-2 sequence boosts the effector immune response; this shifts the balance by further decreasing the immune suppression ‖↔‖ E2, estradiol; Thl, T helper type 1 cell; Th2, T helper type 2 cell; M1 TAM, type 1 tumor associated macrophage; M2 TAM, type 2 tumor associated macrophage; CAF, cancer associated fibroblast; MDSC, myeloid-derived suppressor cell, APC, antigen presenting cell; ROS, reactive oxygen species, IDO, indoleamine-pyrrole 2, 3 dioxygenase; NO, nitric oxide; IL, interleukin; TME, tumor microenvironment; TGFbeta, transforming growth factor beta; TNFalpha, tumor necrosis factor alpha; NFkB, nuclear factor k light-chain enhancer of activated B cells; COX2, cyclooxygenase-2; PGE2, prostaglandin E2.

Figure 2

Mechanistic rationale for the successful immune manipulation with the addition of IFN-beta-IL-2 sequence to antiestrogens in ER positive breast cancer. (A) E2 from PB (A) and TME (b-c loops) foster tumor growth, invasion, IS. and angiogenesis mostly through ERalpha mediated actions (genomic and non genomic pathways) and some other mechanisms in ER+BCCS; TME, mainly CAFS, TAMs, immune cells and APCs further contribute with production and secretion of inflammatory cytokines (IL-1, IL-4, IL-6, IL-8, IL17A, TGFbeta, TNFalpha, NFKB, COX2, PGE2), suppressive mediators (ROS, IDO, NO, IL-10) as well as other described mechanisms. (B) In patients in clinical benefit during ae., the induced G0-G1 state downregulates the ERalpha mediated actions with stable or decreased T.B. (C) The addition of IFNbeta-IL-2 sequence to ae. boosts the immune response through induced proliferation and activation of the effector immune cells; it derives a stable t b. with delayed hormone resistance or decreased tb. and delayed hormone resistance. E2, estradiol; ER, estrogen receptor; ac., anti estrogen; ER+ BCCS, ER positive breast cancer cells; PB, peripheral blood; I.S., immune suppression (inclusive of immune evasion and immune inhibition); TME ci., tumor microenvironment chronic inflammation; HLA, human leucocyte antigen; IFN, interferon; IL, interleukin; IDO indoleamine-pyrrole 2, 3 dioxygenase; ROS, reactive oxygen species; NO, nitric oxide; TNF alpha, tumor necrosis factor alpha; TGFbeta, transforming growth factor beta; NFKB, nuclear factor k light-chain enhancer of activated B cells; COX2, cyclooxygenase-2; PGE2, prostaglandin E2; CAFs, cancer associated fibroblasts; TAMs, tumor-associated macrophages; M2, type 2 TAM; VEGF, vascular endothelial growth factor; MDSCs, myeloid-derived suppressor cells; Th2, type 2 T helper cell; PI-9, proteinase inhibitor 9; FOX-p3, forkhead box p3; APC, antigen presenting cell; tb., tumor burden; dhr., delayed hormone resistance; CTL, cytotoxic T lymphocyte; a1, autocrine loop in ER+BCCs sustained by increased TNFalpha-E2 production; a2, autocrine loop in TAMs sustained by E2 increased VEGF; b-c, paracrine loops promoting tumor growth, invasion, angiogenesis and IS (functions additional to those mediated by genomic and non genomic pathways in ER+ BCCs).