Tumour-infiltrating lymphocytes in melanoma prognosis and cancer immunotherapy

Lee, Nayoung; Zakka, Labib R.; Mihm, Martín C.; Schatton, Tobias

doi:10.1016/j.pathol.2015.12.006

Cited by 216 publications

(187 citation statements)

References 112 publications

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“…In many cancers an immune infiltrate within the tumor is typically associated with a better prognosis and with response to immunotherapy (Lee et al, 2016). In primary UM, in contrast, marker-specific immunohistochemistry has demonstrated that a dense infiltrate of leukocytes (Bronkhorst et al, 2012; Ksander et al, 1998) or macrophages (Bronkhorst et al, 2011; Maat et al, 2008) is associated with M3 and a poor prognosis.…”

Section: Discussionmentioning

confidence: 99%

Integrative Analysis Identifies Four Molecular and Clinical Subsets in Uveal Melanoma

Robertson¹,

Shih²,

Yau³

et al. 2017

Cancer Cell

708

712

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SUMMARY Comprehensive multiplatform analysis of 80 uveal melanomas (UM) identifies four molecularly distinct, clinically relevant subtypes: two associated with poor-prognosis monosomy 3 (M3) and two with better-prognosis disomy 3 (D3). We show that BAP1 loss follows M3 occurrence and correlates with a global DNA methylation state that is distinct from D3-UM. Poor-prognosis M3-UM divide into subsets with divergent genomic aberrations, transcriptional features, and clinical outcomes. We report change-of-function SRSF2 mutations. Within D3-UM, EIF1AX- and SRSF2/SF3B1 -mutant tumors have distinct somatic copy number alterations and DNA methylation profiles, providing insight into the biology of these low-versus intermediate-risk clinical mutation subtypes.

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Section: Discussionmentioning

confidence: 99%

Integrative Analysis Identifies Four Molecular and Clinical Subsets in Uveal Melanoma

Robertson¹,

Shih²,

Yau³

et al. 2017

Cancer Cell

708

712

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“…Once activated in secondary lymphoid organs, by tumor antigens presentation from specialised cells, CD8 + cells migrate into the tumor mass, looking for tumor cells to kill. Infiltrating CTLs are known as tumor infiltrating lymphocytes (TILs) and have been associated with better survival outcome in various melanomas and carcinomas [194,195]. Interestingly, TILs are becoming an interesting target for adoptive cell immunotherapy (ACI) [196].…”

Section: Mitochondrial Dynamics In T Cell Functionmentioning

confidence: 99%

The mitochondrial dynamics in cancer and immune-surveillance

Simula

Nazio

Campello

2017

Seminars in Cancer Biology

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A B S T R A C TMitochondria-shaping proteins control the dynamic equilibrium between fusion and fission of the mitochondrial network. Their balance is strictly required to regulate various processes, including the quality of mitochondria, cell metabolism, cell death, proliferation and cell migration. Alterations in these processes are frequently encountered in cancer, during both its onset and later progression, as evidence emerge connecting alterations in mitochondrial dynamics with cancer development. In recent years, novel therapeutic approaches to fight against different human tumors aim at exploiting the immune system's ability to specifically recognize tumor antigens, thus killing malignant cells in a process named immune-surveillance. Interestingly, data are accumulating on the role that mitochondrial dynamics play also for the correct function of both the innate and the adaptive immune system. By this review, we overview how mitochondrial dynamics can affect various processes during cancer development, acting directly on tumor cells or indirectly on cells responsible for tumor aggression and defence.

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“…More recently, the term TIL has been used to describe a variety of tumor-infiltrating cells including T cells, T regulatory (T reg ) cells, natural killer (NK) cells, and B cells, as well as macrophages, dendritic cells (DC), and myeloid-derived suppressor cells (MDSC). 4 Herein we use the term ‘TIL’ in reference selectively to the lymphocytotoxic arm of tumor immunity comprised of cytotoxic CD8 + T effector (T eff ) cells given their robust tumoricidal and peripheral tissue homing capacity, characteristics not typically found in related CD8 + central memory T cell subsets (T cm ). 5–8 This emphasis on T eff also does not overlook the fact that all TILs, including NK cells, play participatory roles at the tumor-immune synapse in cancer immunoreactivity and by extension in enhancing or blunting responses to immunotherapy, but underscores the fact that the final most prominent and comprehensively analyzed anti-tumor attack is exerted by cytotoxic lymphocytes (primarily CD8 + T eff ) and supported by NK as well as CD4 + T cells of Th1 (IFN-γ)-producing phenotype.…”

Section: Introductionmentioning

confidence: 99%

“…In support, while circulating T cell numbers and activation status in peripheral blood alone do not routinely coincide with either anti-tumor activity, prognosis or survival as originally thought, TIL frequency, density, spatial localization, and subset ratio intrinsically within tissue of melanoma and other solid tumors correlates well with favorable prognosis and immunotherapeutic responses. 4,14 Indeed, the ratio of intralesional CD8 + T cells to either T reg or CD4 + T cells has been construed as a superior predictive criterion of patient outcome than conventional tumor-node-metastasis (TNM) staging. 9,15 Thus, immunotherapeutic success critically hinges upon efficient homing of TIL or ACT eff cell subsets from the circulation into the inflamed tumor compartment.…”

Section: Introductionmentioning

confidence: 99%

T-lymphocyte homing: an underappreciated yet critical hurdle for successful cancer immunotherapy

Sackstein

Schatton

Barthel

2017

Laboratory Investigation

Self Cite

179

151

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Advances in cancer immunotherapy have offered new hope for patients with metastatic disease. This unfolding success story has been exemplified by a growing arsenal of novel immunotherapeutics, including blocking antibodies targeting immune checkpoint pathways, cancer vaccines, and adoptive cell therapy (ACT). Nonetheless, clinical benefit remains highly variable and patient-specific, in part, because all immunotherapeutic regimens vitally hinge on the capacity of endogenous and/or adoptively-transferred T effector (Teff) cells, including chimeric antigen receptor (CAR) T cells, to home efficiently into tumor target tissue. Thus, defects intrinsic to the multi-step T cell homing cascade have become an obvious, though significantly underappreciated contributor to immunotherapy resistance. Conspicuous have been low intralesional frequencies of tumor-infiltrating T-lymphocytes (TILs) below clinically beneficial threshold levels, and peripheral rather than deep lesional TIL infiltration. Therefore, a Teff cell ‘homing deficit’ may arguably represent a dominant factor responsible for ineffective immunotherapeutic outcomes, as tumors resistant to immune-targeted killing thrive in such permissive, immune-vacuous microenvironments. Fortunately, emerging data is shedding light into the diverse mechanisms of immune escape by which tumors restrict Teff cell trafficking and lesional penetrance. In this review, we scrutinize evolving knowledge on the molecular determinants of Teff cell navigation into tumors. By integrating recently described, though sporadic information of pivotal adhesive and chemokine homing signatures within the tumor microenvironment with better established paradigms of T cell trafficking under homeostatic or infectious disease scenarios, we seek to refine currently incomplete models of Teff cell entry into tumor tissue. We further summarize how cancers thwart homing to escape immune-mediated destruction and raise awareness of the potential impact of immune checkpoint blockers on Teff cell homing. Finally, we speculate on innovative therapeutic opportunities for augmenting Teff cell homing capabilities to improve immunotherapy-based tumor eradication in cancer patients, with special focus on malignant melanoma.

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Tumour-infiltrating lymphocytes in melanoma prognosis and cancer immunotherapy

Cited by 216 publications

References 112 publications

Integrative Analysis Identifies Four Molecular and Clinical Subsets in Uveal Melanoma

Integrative Analysis Identifies Four Molecular and Clinical Subsets in Uveal Melanoma

The mitochondrial dynamics in cancer and immune-surveillance

T-lymphocyte homing: an underappreciated yet critical hurdle for successful cancer immunotherapy

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