Where have all the T cells gone? Mechanisms of immune evasion by tumors

doi:10.1016/S0167-5699(98)01435-2

Immunology Today

Volume 20, Issue 4, 1 April 1999, Pages 158-160

Immunology Today

https://doi.org/10.1016/S0167-5699(98)01435-2 Get rights and content

Abstract

The immune system of tumor-bearing patients and experimental animals is adversely affected by the tumor, even early in the course of disease. A recent meeting* focused on the mechanisms involved in this phenomenon and their implications for cancer immunotherapy.

Section snippets

Immune dysfunction in cancer patients: antigen-specific and generalized effects

Four decades of research leave little doubt that the immune response to tumor antigens, and probably to other antigens, is altered in patients with cancer. However, this diminished immune response in cancer patients is clearly different from the generalized immunosuppression seen in patients receiving high doses of corticosteroids or chemotherapy. The term ‘immune dysfunction’ appears to more adequately describe the observed changes in immune function. In addition, it is apparent that immune

Barriers that prevent tumor recognition

Recent evidence indicates that the immune system is incapable of recognizing some antigen-expressing experimental tumors, even in the presence of a robust, antigen-specific, systemic immune response induced with another form of the tumor antigen (L. Chen, Rochester, MN; H. Schreiber, Chicago, IL)⁷. This phenomenon of immunological ignorance appears to be mediated by the tumor cells and/or local barriers involving the tumor stroma⁸. Cytokines such as transforming growth factor β (TGF-β) might

What is the clinical relevance of immune dysfunction?

The association between alterations in signal transduction molecules and stage of disease has been previously reported (Kiessling). In a large cohort of 140 head and neck cancer patients with metastases, those who expressed normal levels of ζ chain had a distinct survival advantage over those who showed ζ chain loss (Whiteside). Data from renal cell carcinoma patients treated with an IL-2-based therapy showed that only those with a complete response re-expressed normal levels of ζ chain

Conclusion

The effect that a progressively growing tumor has on the immune response presents an important challenge to the success of T-cell-based immunotherapy and cancer vaccines. The immune dysfunction in cancer is distinct from the generalized immunosuppression induced through pharmacological means. Insights into immune responsiveness in cancer patients or tumor-bearing mice have started to provide possible molecular mechanisms that lead to the development of a dysfunctional immune response; however,

Acknowledgements

The workshop ‘Mechanisms of Immune Evasion by Tumors’ was sponsored by the Cancer Immunology Branch of the National Cancer Institute.

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The role of tumor-associated macrophages (TAMs) in tumor progression and relevant advance in targeted therapy
2020, Acta Pharmaceutica Sinica B
Citation Excerpt :
Thus, enhancing immunity not only fail to get objective remission of cancer but also trigger severe immune-related side effects (irAE)7. With the guard of these tricks, so called "immune evasion mechanisms", tumor cells will disrupt the routine immune processes, such as altering the antigen presentation process, secreting immunosuppressive factors that induce lymphocyte apoptosis, or activating adverse regulatory pathways8,9. These immune evasion mechanisms continue to develop and become more diverse and complex during cancer progression.
Macrophages have a leading position in the tumor microenvironment (TME) which paves the way to carcinogenesis. Initially, monocytes and macrophages are recruited to the sites where the tumor develops. Under the guidance of different microenvironmental signals, macrophages would polarize into two functional phenotypes, named as classically activated macrophages (M1) and alternatively activated macrophages (M2). Contrary to the anti-tumor effect of M1, M2 exerts anti-inflammatory and tumorigenic characters. In progressive tumor, M2 tumor-associated macrophages (TAMs) are in the majority, being vital regulators reacting upon TME. This review elaborates on the role of TAMs in tumor progression. Furthermore, prospective macrophage-focused therapeutic strategies, including drugs not only in clinical trials but also at primary research stages, are summarized followed by a discussion about their clinical application values. Nanoparticulate systems with efficient drug delivery and improved antitumor effect are also summed up in this article.
Myeloid-derived suppressor cells in human peripheral blood: Optimized quantification in healthy donors and patients with metastatic renal cell carcinoma
2015, Immunology Letters
Induction of myeloid-derived suppressor cells is an important mechanism leading to tolerance against tumors. Phenotypic characterization of MDSC has been established and heterogeneous populations with monocytic or granulocytic features have been characterized. Increased levels of MDSC have been described in metastatic renal cell carcinoma and seem to correlate with an adverse outcome. As MDSC constitute only small populations in peripheral blood of cancer patients, it is highly important to achieve technically optimized conditions for quantification. Different cell preparation techniques – besides freezing and thawing – are potential sources of substantial variation. Our study was focused on an optimized quantification of MDSC in pB of healthy donors and patients with mRCC, in whom major technical sources of variation were analyzed.
Whole blood and peripheral blood mononuclear cells were used for the flow cytometric quantification of MDSC in the pB of mRCC patients and healthy donors. We compared (1) analysis in whole blood vs. PBMC after Ficoll gradient centrifugation and (2) immediate analysis after blood drawing vs. analysis one day later. Finally, in order to evaluate our optimized technical approach, pB of 15 patients with histologically confirmed mRCC under treatment with either sunitinib or sorafenib was analyzed.
No difference in the number of MDSC was observed after analysis in whole blood vs. PBMC. In contrast, the time point of analysis was a source of substantial variation (one day later vs. immediate analysis after blood drawing).
In conclusion, for optimal analysis of MDSC, immediate analysis of whole blood after blood drawing rather than one day later seems to be most appropriate under the aspect of practical feasibility and reliability. Using this method, we were able to confirm both (a) increased numbers of MDSC in patients with mRCC and (b) a decrease of MDSC under sunitinib therapy.
Disease relevance of T11TS-induced T-cell signal transduction through the CD2-mediated calcineurin-NFAT pathway: Perspectives in glioma immunotherapy
2015, Molecular Immunology
Malignant glioma is the most lethal of a wide array of CNS neoplasms. Its onset and progression are markedly associated with profound immunosupression and paralysis of T-cell survival and proliferation. Myriad immunotherapeutic strategies are presently used to target such T-cell anomalies in glioma. Our recent work has highlighted use of the novel glycopeptide, the CD2 ligand, T11 target structure (T11TS) as an immunotherapeutic agent against experimentally induced glioma in rats. We have shown that T11TS causes multi-target modulation of key components of the T-cell – antigen presenting cell (APC) immunological synapse. This consequently triggers T-cell activation so as to reverse glioma-induced changes to physiological levels. T11TS administration also causes CD2 upregulation. Earlier we also found T11TS to cause enhanced proliferation of both CD4+ and CD8+ T-cells in glioma conditions. These findings led us to believe that downstream CD2-stimulated “alternative pathway” of calcineurin–NFAT could be a possible target for modulation by T11TS. In the present paper we thus show that immunotherapy with T11TS induces a multi-targeted approach towards activation of this “alternative pathway” of T-cell signaling providing an immunotherapeutic advantage against glioma. We show here that T11TS immunotherapy causes positive modulations of the CD2 pathway-associated proteins, viz., p59fyn, protein kinase C-θ (PKC-θ), calcineurin and nuclear factor for activation of T-cells (NFAT) and hint that this may accord greater survival and proliferation advantage to T-cells of the glioma-bearing animals for augmented defence against glioma. These findings help open a molecular immunotherapeutic door – one which is directed towards clinical studies for glioma-immunotherapy using T11TS.
Antitumor immunostimulatory activity of polysaccharides from Salvia chinensis Benth
2015, Journal of Ethnopharmacology
Salvia chinensis Benth (S. chinensis) is a traditional herb applied in the treatment of hepatocellular carcinoma (HCC). Polysaccharides abundantly exist in this plant. However, it remains poorly understood if polysaccharides from S. chinensis (PSSC) contribute to its anti-HCC activity.
The in vivo anti-HCC activity of PSSC was evaluated in Kunming mice bearing H22 ascitic hepatoma cells. An array of physiological indexes was measured to evaluate toxicological effects on host animals. Subgroups of immune cells were purified by a magnetic-activated cell sorting system and analyzed by flow cytometry. Reverse transcription real-time PCR and immunoblotting were recruited to determine the effects of PSSC on the cellular signaling of different subgroup of immune cells.
PSSC suppressed in vivo proliferation of H22 cells with undetectable toxic effects on tumor-bearing mice. PSSC alleviated tumor transplantation-induced CD4+ T cell apoptosis and dysregulation of serum cytokine profiles, which elevated cytotoxic activities of natural killer and CD8+ T cells. PSSC reduced serum levels of prostaglandin E2 (PGE2). Injection of exogenous PGE2 completely abrogated the antitumor immunostimulatory activity of PSSC. Cyclic adenosine monophosphate (cAMP) is the second messager of PGE2. In CD4+ T cells, PSSC substantially declined intracellular cAMP. This event elevated protein levels of JAK3, enhancing STAT5 phosphorylation and STAT5-depedent expression of anti-apoptotic genes. Cyclooxygenase-2 is the key enzyme mediating biosynthesis of PGE2. PSSC suppressed the transcription and translation of cyclooxygenase-2 in tumor associated macrophages.
Our data clearly showed antitumor immunostimulatory activity of PSSC against transplanted H22 HCC cells. Suppressing tumor transplantation-induced PGE2 production was implicated in the anti-tumor immunostimulatory activity of PSSC. These works provides novel insights into the traditional application of S. chinensis against HCC and supported considering PSSC as an adjuvant reagent in clinical HCC treatment.
Locoregional surgery for stage IV breast cancer patients
2015, Gynecologie Obstetrique et Fertilite
Le cancer du sein stade IV concerne 3 à 6 % des nouveaux cas. La survie est de 16 à 45 mois. Elle dépend du nombre et du site des métastases, avec une tendance à l’amélioration ces dernières années. Jusqu’au début des années 2000, la chirurgie locorégionale était réservée aux soins de confort (saignements ou ulcérations invalidantes), chirurgie dite de propreté. Des études rétrospectives ont comparé le pronostic des patientes ayant un cancer du sein stade IV avec ou sans chirurgie locorégionale. La majorité des études montre une amélioration de la survie globale chez les patientes opérées. Toutefois, il existe de nombreux biais dans ces études, notamment de sélection. Les patientes de meilleur pronostic ont bénéficié d’une chirurgie rendant difficile l’analyse de la part de la chirurgie dans l’amélioration de la survie. Plusieurs essais prospectifs sont en cours. Les résultats partiels ne sont pas en faveur de la chirurgie. Toutefois, la chirurgie mammaire étant peu morbide, en dehors de l’aspect psychologique d’une mastectomie, elle peut être proposée chez des patientes stables ou en régression sous chimiothérapie. Un traitement conservateur est envisageable mais doit être optimal avec des berges de résection saines. L’intérêt d’un geste axillaire, potentiellement morbide, n’a jamais été démontré. Enfin, l’intérêt de la radiothérapie a été étudié de façon rétrospective mais semble donner les mêmes bénéfices en termes de survie que la chirurgie. Elle peut constituer seule ou en association à la chirurgie une option de traitement locorégionale dans les cancers du sein stade IV.
Three to 6% of women newly diagnosed with breast cancers have stage IV disease. Overall survival was improved during the last few years (16–45 months). The treatment of stage IV breast cancer has traditionally been palliative with surgical resection reserved for symptomatic wound complications. Since 2000, several retrospective studies have compared surgery versus no local therapy in women presenting with stage IV breast cancer with an intact primary tumor. All showed a survival advantage for the surgical cohort. However, these studies are limited by the fact that it is not possible to control for biases that led to surgical resection of the primary tumor. Several prospective randomized trials have been undertaken. We have partial results for two of them and they show no survival differences between patients who benefit from local surgery and patients who did not have surgery. However, breast surgery is at low risk of complication, if not considering psychological aspect of mastectomy, and can be proposed to patients with no progression after first chemotherapy. Conservative management can be an option, but surgery must be optimal with negative margins. No benefit of axillary surgery has been shown but this treatment can lead to complications and impact quality of life of patients. Therefore, axillary node resection is not recommended for stage IV breast cancer. Finally, radiotherapy can be an alternative option of local therapy associated or no to surgery in stage IV breast cancer.
The significant immunological characteristics of peripheral blood neutrophil-to-lymphocyte ratio and Fas ligand expression incidence in nephrectomized tumor in late recurrence from renal cell carcinoma
2013, Urologic Oncology: Seminars and Original Investigations
Citation Excerpt :
Therefore, Fas-mediated apoptosis activated by FasL is closely related to the cancer cell apoptosis induced by immunotherapy. However, it is well known that malignant cells use various mechanisms in order to evade immunity and grow progressively [5,6]. Although the Fas lytic pathways has been suggested to play a crucial role in the function of CTLs in animal-based renal cell carcinoma (RCC) models [7], there have been few investigations of its clinical significance based on actual patient data and surgical specimens.
In order to characterize the significance of immune system function in patients with advanced renal cell carcinoma (RCC), we investigated the interactive relationships among the following parameters: metastatic characteristics, expression of Fas ligand (FasL) in nephrectomized specimens, immunological parameters, and patient's prognosis.
Thirty-five patients with advanced RCC were stratified into 3 groups according to the characteristics of metastasis timing, at first presentation (mFP), within 5 years of nephrectomy (early-recurrence), after 5 years (late-recurrence). Immunological parameters [hemoglobin, lymphocyte count, neutrophil/lymphocyte ratio (NLR), serum albumin, Eastern Cooperative Oncology Group (ECOG) performance status (PS), and Charlson Comorbidity Index], FasL expression in RCC, and patient prognosis from occurrence of metastasis were compared among the groups. Thirty-five patients were also stratified into 2 groups according to FasL positivity and individual parameters. Patient's prognosis and the remaining immunological parameters were compared between groups.
The NLRs of the late-recurrence group were significantly lower than those of the mFP (P = 0.0004) and early-recurrence (P = 0.013) groups. The FasL mRNA positivity of the late-recurrence group was significantly lower than those of the mFP (P = 0.001) and early-recurrence (P = 0.0277) groups. The prognosis of the late-recurrence group was significantly better than that of the early-recurrence group (P = 0.0255). NLRs were significantly lower in the FasL-negative group than in the -positive group (P = 0.0182). The cause-specific survival rates of the ECOG PS 0 group were significantly higher than that of the ECOG PS > 0 group (P < 0.0001).
Our results suggest the associations of the prognosis in advanced RCC with peripheral blood NLR and FasL expression in nephrectomized tumor. The characteristics of lower values of NLR and FasL expression positivity in late-recurrence compared with other metastatic timings suggest strong host immune activity, and may imply relatively long survival. On the other hand, elucidation of the patient's general condition obtained not only by chemical data but also by ECOG PS is crucial in the management of patients with advanced RCC.

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^*: The workshop ‘Mechanisms of Immune Evasion by Tumors’ was held in Washington, DC, USA, on 1–2 September 1998.

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TrendsWhere have all the T cells gone? Mechanisms of immune evasion by tumors

Abstract

Section snippets

Immune dysfunction in cancer patients: antigen-specific and generalized effects

Barriers that prevent tumor recognition

What is the clinical relevance of immune dysfunction?

Conclusion

Acknowledgements

Life Sci.

Immunol. Today

Blood

Cell. Immunol.

Proc. Natl. Acad. Sci. U. S. A.

J. Exp. Med.

Cancer Res.

Trends
Where have all the T cells gone? Mechanisms of immune evasion by tumors