Immunomodulation via FGFR inhibition augments FGFR1 targeting T-cell based antitumor immunotherapy for head and neck squamous cell carcinoma

Kono, Michihisa; Komatsuda, Hiroki; Yamaki, Hidekiyo; Kumai, Takumi; Hayashi, Ryusuke; Wakisaka, Risa; Nagato, Toshihiro; Ohkuri, Takayuki; Kosaka, Akemi; Ohara, Kenichi; Kishibe, Kan; Takahara, Miki; Katada, Akihiro; Hayashi, Tatsuya; Kobayashi, Hiroya; Harabuchi, Yasuaki

doi:10.1080/2162402x.2021.2021619

Cited by 20 publications

(20 citation statements)

References 49 publications

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“…Because inhibition of MAPK also increased HLA‐DR expression in tumors (Figure 5B), it is plausible that HOXB7 suppresses tumoral HLA‐DR through MAPK. As we previously reported, inhibition of MAPK increases CIITA expression in tumor 35 . However, only HPC92Y cells showed an increase in CIITA by HOXB7 inhibition alone, while IFN‐γ was required for the other cell lines (Figure S6).…”

Section: Resultssupporting

confidence: 66%

“…Wang et al reported that HOXB7 activates the MAPK pathway through the induction of bFGF secretion following FGFR3 stimulation, and suppression of bFGF inhibits HOXB7 ‐induced MAPK activation. 41 As we previously identified that FGFR1 was expressed in HNSCC cells, 35 FGFR3 was not expressed in HNSCC cells (data not shown). Thus, FGFR3 could be dispensable in the HOXB7 /MAPK pathway.…”

Section: Discussionmentioning

confidence: 81%

“…As we previously reported, inhibition of MAPK increases CIITA expression in tumor. 35 However, only HPC92Y cells showed an increase in CIITA by HOXB7 inhibition alone, while IFN‐γ was required for the other cell lines (Figure S6 ). As STAT1 phosphorylation was also elevated in accordance with CIITA expression, HOXB7 may suppress MHC class II expression through the MAPK and/or IFN‐γ pathway (Figure 5C ).…”

Section: Resultsmentioning

confidence: 98%

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Mitogen‐activated protein kinase inhibition augments the T cell response against HOXB7‐expressing tumor through human leukocyte antigen upregulation

et al. 2022

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Homeobox B7 (HOXB7) is a master regulatory gene that regulates cell proliferation and activates oncogenic pathways. Overexpression of HOXB7 correlates with aggressive behavior and poor prognosis in patients with cancer. However, the expression and role of HOXB7 in head and neck squamous cell carcinoma (HNSCC) remain unclear. In this study, we observed that most samples from patients with oropharyngeal cancer and HNSCC expressed HOXB7. As no direct inhibitor has been reported, we identified a potent peptide epitope to target HOXB7-expressing tumors through immune cells. A novel HOXB7-derived peptide epitope (HOXB7 8-25 ) elicited antigenspecific and tumor-reactive promiscuous CD4 + T cell responses. These CD4 + T cells produced γ-interferon (IFNγ) and had the direct ability to kill tumors through granzyme B. Notably, downregulation of HOXB7 using siRNA enhanced human leukocyte antigen class II expression on tumor cells by decreasing the phosphorylation of MAPK.Mitogen-activated protein kinase inhibition augmented IFNγ production by HOXB7reactive CD4 + T cell responses without decreasing the expression of HOXB7. These results suggest that combining HOXB7 peptide-based vaccine with MAPK inhibitors could be an effective immunological strategy for cancer treatment.

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Section: Resultssupporting

confidence: 66%

Section: Discussionmentioning

confidence: 81%

Section: Resultsmentioning

confidence: 98%

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Mitogen‐activated protein kinase inhibition augments the T cell response against HOXB7‐expressing tumor through human leukocyte antigen upregulation

et al. 2022

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“…Regarding the role of FGFR in the interaction of tumor cells and TME, including CAFs, it is also reasonable to assume that FGFR inhibitors could indirectly target CAFs [ 245 , 246 ]. Data have shown that FGFR inhibition, for example FGFR1 inhibitors, can lead to immunomodulation by triggering T-cell-based antitumor activity [ 247 ].…”

Section: Crc-associated Fibroblasts—therapeutic Implications and Clin...mentioning

confidence: 99%

Cancer-Associated Fibroblasts: The Origin, Biological Characteristics and Role in Cancer—A Glance on Colorectal Cancer

Fotsitzoudis

Koulouridi

Messaritakis

et al. 2022

Cancers

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The therapeutic approaches to cancer remain a considerable target for all scientists around the world. Although new cancer treatments are an everyday phenomenon, cancer still remains one of the leading mortality causes. Colorectal cancer (CRC) remains in this category, although patients with CRC may have better survival compared with other malignancies. Not only the tumor but also its environment, what we call the tumor microenvironment (TME), seem to contribute to cancer progression and resistance to therapy. TME consists of different molecules and cells. Cancer-associated fibroblasts are a major component. They arise from normal fibroblasts and other normal cells through various pathways. Their role seems to contribute to cancer promotion, participating in tumorigenesis, proliferation, growth, invasion, metastasis and resistance to treatment. Different markers, such as a-SMA, FAP, PDGFR-β, periostin, have been used for the detection of cancer-associated fibroblasts (CAFs). Their detection is important for two main reasons; research has shown that their existence is correlated with prognosis, and they are already under evaluation as a possible target for treatment. However, extensive research is warranted.

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“…Less evidence associates the expression of FGFR and immune modulation. In one study, FGFR inhibition augmented T cell immune response ( 76 ). However, in both cases, a direct correlation of these receptors with Type 2 T-helper populations has not been described.…”

Section: Discussionmentioning

confidence: 99%

Genomic mapping of copy number variations influencing immune response in breast cancer

et al. 2022

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Identification of genomic alterations that influence the immune response within the tumor microenvironment is mandatory in order to identify druggable vulnerabilities. In this article, by interrogating public genomic datasets we describe copy number variations (CNV) present in breast cancer (BC) tumors and corresponding subtypes, associated with different immune populations. We identified regulatory T-cells associated with the Basal-like subtype, and type 2 T-helper cells with HER2 positive and the luminal subtype. Using gene set enrichment analysis (GSEA) for the Type 2 T-helper cells, the most relevant processes included the ERBB2 signaling pathway and the Fibroblast Growth Factor Receptor (FGFR) signaling pathway, and for CD8+ T-cells, cellular response to growth hormone stimulus or the JAK-STAT signaling pathway. Amplification of ERBB2, GRB2, GRB7, and FGF receptor genes strongly correlated with the presence of type 2 T helper cells. Finally, only 8 genes were highly upregulated and present in the cellular membrane: MILR1, ACE, DCSTAMP, SLAMF8, CD160, IL2RA, ICAM2, and SLAMF6. In summary, we described immune populations associated with genomic alterations with different BC subtypes. We observed a clear presence of inhibitory cells, like Tregs or Th2 when specific chromosomic regions were amplified in basal-like or HER2 and luminal groups. Our data support further evaluation of specific therapeutic strategies in specific BC subtypes, like those targeting Tregs in the basal-like subtype.

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Immunomodulation via FGFR inhibition augments FGFR1 targeting T-cell based antitumor immunotherapy for head and neck squamous cell carcinoma

Cited by 20 publications

References 49 publications

Mitogen‐activated protein kinase inhibition augments the T cell response against HOXB7‐expressing tumor through human leukocyte antigen upregulation

Mitogen‐activated protein kinase inhibition augments the T cell response against HOXB7‐expressing tumor through human leukocyte antigen upregulation

Cancer-Associated Fibroblasts: The Origin, Biological Characteristics and Role in Cancer—A Glance on Colorectal Cancer

Genomic mapping of copy number variations influencing immune response in breast cancer

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