Myeloid immune cells are frequently present in the tumor environment, and although they can positively contribute to tumor control they often negatively impact anticancer immune responses. One way... Show moreMyeloid immune cells are frequently present in the tumor environment, and although they can positively contribute to tumor control they often negatively impact anticancer immune responses. One way of inhibiting the positive contributions of myeloid cells is by signaling through the cluster of differentiation 47 (CD47)/signal regulatory protein alpha (SIRP alpha) axis. The SIRP alpha receptor is expressed on myeloid cells and is an inhibitory immune receptor that, upon binding to CD47 protein, delivers a 'don't eat me' signal. As CD47 is often overexpressed on cancer cells, treatments targeting CD47/SIRP alpha have been under active investigation and are currently being tested in clinical settings. Interestingly, the CD47/SIRP alpha axis is also involved in T cell-mediated antitumor responses. In this perspective we provide an overview of recent studies showing how therapeutic blockade of the CD47/SIRP alpha axis improves the adaptive immune response. Furthermore, we discuss the interconnection between the myeloid CD47/SIRP alpha axis and adaptive T cell responses as well as the potential therapeutic role of the CD47/SIRP alpha axis in tumors with acquired resistance to the classic immunotherapy through major histocompatibility complex downregulation. Altogether this review provides a profound insight for the optimal exploitation of CD47/SIRP alpha immune checkpoint therapy. Show less
Purpose: The association of human leucocyte antigen (HLA) class I expression levels with the clinical course of many malignancies reflects their crucial role in the recognition and elimination of... Show morePurpose: The association of human leucocyte antigen (HLA) class I expression levels with the clinical course of many malignancies reflects their crucial role in the recognition and elimination of malignant cells by cognate T cells and NK cells. In colorectal cancer, results regarding this association are conflicting. The potential pathogenetic and therapeutic implications of this association prompted us to perform a large patient-level pooled analysis assessing the role of the expression level of HLA class I loci gene products in colon and rectal cancer. Experimental design: Included studies provided patient-level data on HLA class I expression levels determined by immunohistochemistry on surgical specimens. Expression levels of the HLA class I loci gene products (HLA-A, HLA-B/C) were correlated with common genetic events and survival. Results: Data from 5 studies including 2863 patients were used. In the 1620 colon cancer patients, lower HLA-A, HLA-B/C and total HLA class I expression levels were associated with microsatellite instability (p=0.044, p=0.008 and p=0.022, respectively), higher frequency of BRAF mutations (p<0.001, p=0.021 and p<0.001, respectively) and lower frequency of KRAS mutations (p=0.001, ns and p=0.002, respectively). In the 1243 rectal cancer patients, HLA-A expression was higher in tumors treated with neoadjuvant radiation (p=0.024). High HLA-B/C, but not HLA-A, expression level was an independent predictor of favorable overall survival in colon (p=0.006) and rectal (p<0.001) cancer. Conclusions: T-cells and HLA-B/C antigens, rather than NK cells and HLA-A antigens, likely play an important role in controlling colon/rectal cancer growth. Colon/rectal cancer patients may benefit from strategies that upregulate HLA-B/C and trigger or enhance T cell immunity. Show less
Nejad, E.B.; Labrie, C.; Elsas, M.J. van; Kleinovink, J.W.; Mittrucker, H.W.; Franken, K.L.M.C.; ... ; Burg, S.H. van der 2021
Background High serum interleukin (IL-6) levels may cause resistance to immunotherapy by modulation of myeloid cells in the tumor microenvironment. IL-6 signaling blockade is tested in cancer, but... Show moreBackground High serum interleukin (IL-6) levels may cause resistance to immunotherapy by modulation of myeloid cells in the tumor microenvironment. IL-6 signaling blockade is tested in cancer, but as this inflammatory cytokine has pleiotropic effects, this treatment is not always effective. Methods IL-6 and IL-6R blockade was applied in an IL-6-mediated immunotherapy-resistant TC-1 tumor model (TC-1.IL-6) and immunotherapy-sensitive TC-1.control. Effects on therapeutic vaccination-induced tumor regression, recurrence and survival as well on T cells and myeloid cells in the tumor microenvironment were studied. The effects of IL-6 signaling in macrophages under therapy conditions were studied in Il6ra(fl/fl)xLysM(cre+) mice. Results Our therapeutic vaccination protocol elicits a strong tumor-specific CD8(+) T-cell response, leading to enhanced intratumoral T-cell infiltration and recruitment of tumoricidal macrophages. Blockade of IL-6 signaling exacerbated tumor outgrowth, reflected by fewer complete regressions and more recurrences after therapeutic vaccination, especially in TC-1.IL-6 tumor-bearing mice. Early IL-6 signaling blockade partly inhibited the development of the vaccine-induced CD8(+) T-cell response. However, the main mechanism was the malfunction of macrophages during therapy-induced tumor regression. Therapy efficacy was impaired in Il6ra(fl/fl)xLysM(cre+) but not cre-negative control mice, while no differences in the vaccine-induced CD8(+) T-cell response were found between these mice. IL-6 signaling blockade resulted in decreased expression of suppressor of cytokine signaling 3, essential for effective M1-type function in macrophages, and increased expression of the phagocytic checkpoint molecule signal-regulatory protein alpha by macrophages. Conclusion IL-6 signaling is critical for macrophage function under circumstances of immunotherapy-induced tumor tissue destruction, in line with the acute inflammatory functions of IL-6 signaling described in infections. Show less
Gracht, E.T.I. van der; Schoonderwoerd, M.J.; Duikeren, S. van; Yilmaz, A.N.; Behr, F.M.; Colston, J.M.; ... ; Arens, R. 2020
Background Adenoviral vectors emerged as important platforms for cancer immunotherapy. Vaccination with adenoviral vectors is promising in this respect, however, their specific mechanisms of action... Show moreBackground Adenoviral vectors emerged as important platforms for cancer immunotherapy. Vaccination with adenoviral vectors is promising in this respect, however, their specific mechanisms of action are not fully understood. Here, we assessed the development and maintenance of vaccine-induced tumor-specific CD8(+) T cells elicited upon immunization with adenoviral vectors. Methods Adenoviral vaccine vectors encoding the full-length E7 protein from human papilloma virus (HPV) or the immunodominant epitope from E7 were generated, and mice were immunized intravenously with different quantities (10(7), 10(8) or 10(9) infectious units). The magnitude, kinetics and tumor protection capacity of the induced vaccine-specific T cell responses were evaluated. Results The adenoviral vaccines elicited inflationary E7-specific memory CD8(+) T cell responses in a dose-dependent manner. The magnitude of these vaccine-specific CD8(+) T cells in the circulation related to the development of E7-specific CD8(+) tissue-resident memory T (T-RM) cells, which were maintained for months in multiple tissues after vaccination. The vaccine-specific CD8(+) T cell responses conferred long-term protection against HPV-induced carcinomas in the skin and liver, and this protection required the induction and accumulation of CD8(+) T-RM cells. Moreover, the formation of CD8(+) T-RM cells could be enhanced by temporal targeting CD80/CD86 costimulatory interactions via CTLA-4 blockade early after immunization. Conclusions Together, these data show that adenoviral vector-induced CD8(+) T cell inflation promotes protective T-RM cell populations, and this can be enhanced by targeting CTLA-4. Show less
Kooij, M.K. van der; Speetjens, F.M.; Burg, S.H. van der; Kapiteijn, E. 2019
