Role of tumor-infiltrating lymphocytes in patients with solid tumors: Can a drop dig a stone?

Badalamenti, Giuseppe; Fanale, Daniele; Incorvaia, Lorena; Barraco, Nadia; Listì, Angela; Maragliano, Rossella; Vincenzi, Bruno; Calò, Valentina; Iovanna, Juan; Bazan, Viviana; Russo, Antonio

doi:10.1016/j.cellimm.2018.01.013

Cited by 185 publications

(163 citation statements)

References 101 publications

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“…Still, untypical gene expression patterns in tumor cells are a source of inaccurateness when studying tumor samples, and this can explain why we sometimes get small estimates of cell types not likely present in the tumor microenvironment. Localization of the different immune cells in tumor has also been associated with patient outcome (Badalamenti et al ., ). In our study, we did not have whole sections from the tumors, which hindered us in such investigations.…”

Section: Discussionmentioning

confidence: 99%

The immune microenvironment in non‐small cell lung cancer is predictive of prognosis after surgery

et al. 2019

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The impact of the tumor immune microenvironment on overall survival in non‐small cell lung cancer ( NSCLC ) has been studied, but there is little information on its relevance for risk of relapse after surgery. Understanding more about the immune microenvironment in previously untreated NSCLC could help in identifying high‐risk patients and patients more likely to benefit from neoadjuvant/adjuvant immunotherapy. Here, we examined gene expression in 399 surgically derived NSCLC samples and 47 samples from normal lung, using Agilent microarray and RNA sequencing. In 335 of the tumor samples, programmed death‐ligand 1 ( PD ‐L1) expression was evaluated by immunohistochemistry. Gene expression was used to estimate content of immune cells and to calculate an immune score. Properties of the immune microenvironment, and its impact on prognosis, were compared in histological subgroups and gene expression subtypes. Tumors with an active immune microenvironment were found for both adenocarcinomas ( AD ) and squamous cell carcinomas ( SCC ). In AD , high immune score and high estimates of several immune cell types belonging to the adaptive immune system were associated with better progression‐free survival ( PFS ), while in SCC , no association between immune characteristics and PFS was found. The immune microenvironment, including PD ‐L1 expression, and its impact on prognosis showed clear differences in AD and SCC gene expression subtypes. In conclusion, the NSCLC immune microenvironment is predictive of prognosis after surgery. Lung AD and SCC gene expression subtypes should be investigated as potential prognostic biomarkers in patients treated with immune checkpoint inhibitors.

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Section: Discussionmentioning

confidence: 99%

The immune microenvironment in non‐small cell lung cancer is predictive of prognosis after surgery

et al. 2019

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“…The maintenance of an immunosuppressive microenvironment has an important role in carcinogenesis in general and also in HPV‐associated carcinogenesis . Tumor‐associated macrophages (TAMs), tumor‐infiltrating lymphocytes, and tumor‐associated neutrophils (TANs) are observed in several types of cancers . Depending on the dominant cellular subtypes, protumor or antitumor effects are expected .…”

Section: Discussionmentioning

confidence: 99%

Indoleamine 2,3‐dioxygenase and tryptophan 2,3‐dioxygenase expression in HPV infection, SILs, and cervical cancer

Venancio

Consolaro

Derchain

et al. 2019

Cancer Cytopathology

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BACKGROUND: Human papillomavirus (HPV) infection is the central factor for cervical cancer, whereas epithelial immune mechanisms contribute to the progression of HPV infection and its associated lesions. The authors evaluated the expression of indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO) in cervicovaginal samples from women with normal cervical epithelium or with different degrees of squamous intraepithelial lesions (SILs) and cervical cancer. METHODS: IDO expression was analyzed by immunocytochemistry in liquid-based cytology samples from 165 women, of whom 42 had cervical changes subclassified as low-grade SIL (n = 6), high-grade SIL (n = 30), or squamous cell carcinoma (SCC) (n = 6), and 123 had negative Papanicolaou smears. IDO and TDO expression also were analyzed by immunohistochemistry, and HPV and other genital pathogens were evaluated by polymerase chain reaction analysis. RESULTS: Low IDO expression was observed in normal cervical epithelium irrespective of HPV status. Increased numbers of IDO-positive squamous cells and IDO-positive leukocytes were observed in women with SIL or SCC. TDO expression was detected in leukocytes infiltrating the stroma around intraepithelial or invasive cervical lesions. Higher IDO levels were detected in organotypic epithelial cultures established from keratinocytes transduced with the HPV16 E6/E7 oncoproteins. CONCLUSIONS: The upregulation of IDO expression in leukocytes and squamous cells in HPVassociated SIL and SCC suggests that immunosuppressive mechanisms involving tryptophan metabolism may have a role in cervical carcinogenesis. Although previous studies have suggested the role of IDO in HPV pathogenesis, this is the first evidence of TDO involvement in the process. Furthermore, the current data emphasize the role of leukocytes, especially neutrophil-like cells, as an IDO source.We gratefully acknowledge the collaboration of Luiz Carlos Zeferino, Júlio Cesar Teixeira, and Luiz Bahamondes for their assistance to the women included in this study and Maria Cecília Costa and Fabrícia Gimenez for their assistance with polymerase chain reaction analyses.Additional supporting information may be found in the online version of this article.

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“…Here we used co-cultures of tumor cells with PBMC as an easy assay to mimic tumor infiltrating immune cells. Tumor-infiltrating lymphocytes and monocyte-derived cells are observed in several types of cancers and depending on their phenotype pro-or anti-tumor effects are expected (Galdiero et al ., 2012; Badalamenti et al ., 2018). By the contact with tumor cell, mononuclear cells can be activated and can cause tumor death or arrest that was used to estimate how 1-MT modulate the immune response and affect the tumoricidal activity.…”

Section: Discussionmentioning

confidence: 99%

1-Methyl-tryptophan enantiomers differently affect the cross-talking between mononuclear and tumor cells and interferon-γ production

Msf

Mbb

et al. 2019

Preprint

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2The inhibition of the enzyme indoleamine-2,3-dioxygenase (IDO), that catalyzes the 3 oxidation of the amino acid tryptophan to kynurenine (KYN), is considered a good target 4 for immunoadjuvants in antineoplastic therapy. 1-Methyl-tryptophan (1-MT) is the most 5 studied molecule for this purpose. Although L-1-MT is better than D-1-MT in inhibiting 6 IDO, for an unknown reason the D-enantiomer has higher clinical efficacy. Here we took 7 advantage of co-cultures of tumor cells (SK-Mel 19 melanoma line; 1x10 5 cells/well) with 8 peripheral blood mononuclear cells (PBMC; 5x10 6 cells/well) to verify the effect of 1-9 MT enantiomers on cytokine production and tumoricidal activity. At a concentration that 10 did not affect KYN production, 1-MT (50 µM) affected the production of TNF-α, IL-10, 11 and IFN-γ measured in co-cultures supernatants. Stereospecificity was only observed for 12 IFN-γ production. D-1-MT inhibited more than 30% of IFN-γ production, while L-1-MT 13 had no effect. Stereospecific effect was also seen in PBMC tumoricidal activity, 14 estimated by tumor cell viability (Trypan assay). The racemic mixture DL-and D-1-MT 15 almost doubled the tumoricidal activity of PBMCs, while L-1-MT had no effect. These 16 are previous unknown off-target effects of D-1-MT. Our data suggest the modulation of 17 IFN-γ and the activation of tumor recognition and killing processes by immune cells as 18 important features for the in vivo effects of the D-1-MT. These findings should be 19 considered in future studies of immunoadjuvants for cancer treatment.20 21 22 Keyworks: D-1-methyl-tryptophan; indoleamine-2,3-dioxygenase; Indoximod; 23 interferon-gamma; immunomodulation; PBMC; TNF-; IL-10. 24 25

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Role of tumor-infiltrating lymphocytes in patients with solid tumors: Can a drop dig a stone?

Cited by 185 publications

References 101 publications

The immune microenvironment in non‐small cell lung cancer is predictive of prognosis after surgery

The immune microenvironment in non‐small cell lung cancer is predictive of prognosis after surgery

Indoleamine 2,3‐dioxygenase and tryptophan 2,3‐dioxygenase expression in HPV infection, SILs, and cervical cancer

1-Methyl-tryptophan enantiomers differently affect the cross-talking between mononuclear and tumor cells and interferon-γ production

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