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Determinants of cancer immunotherapy success Expert Rev. Vaccines 9(12), 1363–1366 (2010)
Vaios Karanikas Author for correspondence: Cancer Immunology Unit, Department of Immunology and Histocompatibility, School of Medicine, University of Thessaly, PO Box 1400, GR-41110, Larissa, Greece Tel.: +30 241 068 5718 Fax: +30 241 068 5549
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Anastasios Germenis Cancer Immunology Unit, Department of Immunology and Histocompatibility, School of Medicine, University of Thessaly, PO Box 1400, GR-41110, Larissa, Greece
“Given that cancer patients can mount spontaneous immune responses against their own tumors, it would be expected that responses initiated by immunotherapeutic interventions would explicitly target and destroy tumor cells, while at the same time sparing normal cells.” Immunotherapy aims to stimulate the immune system to direct its efforts towards cancer destruction by boosting pre-existing immune responses specific for tumorassociated antigenic peptides presented to T cells [1] . Such approaches are quite attractive, since current therapies rely on chemotherapeutic drugs that target proliferating cells (both cancerous and normal) in cancer patients [2] . Given that cancer patients can mount spontaneous immune responses against their own tumors, it would be expected that responses initiated by immunotherapeutic interventions would explicitly target and destroy tumor cells, while at the same time sparing normal cells [3] . Advances in our understanding of the interactions between immune components and tumor cells have encouraged the development of such new strategies. Despite enormous progress in the field of immunotherapy, the clinical efficacy of the various cancer immunotherapy modalities remains rather low. A mere 5% of patients demonstrate short-lived tumor regressions after receiving injections of various antigenic peptides [4] , despite several immunopotentiating improvements [5] . Therefore, the question that continues to overshadow immunotherapeutic attempts is: what are the underlying reasons or factors for this ineffectiveness? Progress made over the last decade has implicated tumor escape mechanisms, poor antigen selection for vaccination, inadequate vaccine delivery and others, as possible contributors [5] .
It remains elusive, however, which of these parameters, if any, control the antitumor response and affect the outcome of immunotherapy. Recently, the numbers of pre-existing anti-tumor cytolytic T lymphocytes (CTLs), as well as their functional quality, have both been implicated as likely candidates [6–8] . Moreover, revolutionary knowledge revealing the complexity of T-cell biology, generated during recent years, has recognized the processes of replicative senescence and immunosenescence as critical and capable of severely compromising the hosts’ ability to combat tumors effectively [9] . Hence, it is not unreasonable to consider whether the aforementioned could represent important determinants for the fate of cancer immunotherapy. Improvements in our understanding of how they become affected promise to have a significant impact on the design of future cancer immunotherapy protocols.
“...tumor-specific cytotoxic T lymphocyte clones derived from cancer patients ... presented with a decreased proliferative capacity, intensity of multimer staining and lytic capacity...” The detection of pre-existing antitumor-specific CTL responses in cancer patients is currently used either in the context of evaluating tumor antigens as potential candidates for vaccination [10,11] ,
Keywords : cytolytic T lymphocytes • immunotherapy • pre-existing anti-tumor-specific CTL
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in an attempt to exclude patients with undetectable pre-existing responses from immunotherapy trials [12–14] , or to comparatively ascertain their post-vaccination increase [15,16] . Therefore, it remains questionable whether the distribution and strength of the initial anti-tumor precursor CTL frequency can affect the outcome of anticancer vaccination and this becomes even more complex due to the lack of standardized techniques for measuring them [15,17] . Recent studies from animal models can offer some explanation regarding this parameter.
“...immunosenescence of tumor-specific T cells cannot be underestimated, since it is a complex process that leads to progressive deterioration of immune system components.” Rizzuto et al. have recently demonstrated that the frequency of pre-existing tumor antigen-specific precursor CTLs in mice represents a critical determinant of the quality of the anti-tumor immune response in mouse adoptive-transfer experiments [6] . These findings highlighted that an optimal precursor frequency of anti-tumor-specific T-cell clones exists, under which not only the strongest anti-tumor response can be observed, but which is also capable of dictating several qualitative aspects known to be important for tumor eradication. To this end, we have also examined whether the initial number of anti-tumor-specific CTLs can play a significant role in the anti-tumor response in patients with lung cancer. Using peptide-stimulated blood lymphocyte microcultures and HLA-multimer analysis, the frequency of specific CTLs against naturally processed and presented tumor peptides was measured in newly diagnosed lung cancer patients expressing these antigens [18] compared with age-matched healthy individuals [7,19] . A significantly higher cumulative frequency of circulating peptide-specific CTLs in cancer patients than in healthy individuals was observed. Together with recent evidence from animal models examining the initial T-cell number in the response against pathogens [20,21] , the aforementioned data support the design of studies aiming to evaluate whether the initial pre-existing T-cell frequency can affect the outcome of anticancer vaccination. Another important parameter that has recently been suggested as a critical factor for the success of cancer immunotherapy is the functional status of the anti-tumor CTL [8] . Recent findings from our laboratory support this notion, especially regarding the functional quality of pre-existing anti-tumor CTLs [7] . We observed that tumor-specific CTL clones derived from cancer patients, compared with those derived from healthy individuals, presented with a decreased proliferative capacity, intensity of multimer staining and lytic capacity, indicating a functional impairment in this cell type, as elaborated on later. Regarding the reduced proliferative capacity of the anti-tumorspecific CTL of patients as opposed to healthy individuals, we believe that this could be explained by replicative senescence, a cellular program that limits the proliferation of normal cells, causing them to irreversibly arrest growth and to adopt critical functional changes [22] . This is highly relevant to the immune system and senescent T cells are characterized by irreversible cell-cycle arrest, 1364
short telomeres, resistance to apoptosis, permanent loss of CD28 expression, altered cytokine profiles, reduced ability to respond to stress and various functional changes [23,24] . To this end, Rufer et al. identified two subsets of circulating CD8 + T lymphocytes with an effector phenotype (RA+ CCR7-27+28 +/-) [25] . Although both subsets were mildly lytic and expressed moderate levels of granzyme B, perforin and IFN-g, the population contained predominantly antigen-experienced T cells specific for viral peptides (Epstein–Barr virus and cytomegalovirus), presenting with marked telomere shortening. In another study aiming to establish whether HIV-1 infection and progression is associated with premature aging of memory and naive T cells, it was determined that disease progression was associated with decreased CD28 expression and an increased proportion of late-differentiated antigenexperienced T cells [26] . Both findings suggest that during differentiation of naive to effector cells and subsequently to terminally differentiated effectors, antigen-experienced T cells undergo a series of functional and phenotypic alterations in order to acquire effector function. However, during this process of repetitive stimulation, they are prone to losing their robustness and ability to respond ‘appropriately’ to antigenic challenge.
“...if the efficacy of cancer immunotherapy is to be improved, then one must overcome the dysfunctional ‘senescent T cells’ of cancer patients.” With respect to the increased intensity of multimer staining and lytic capacity of tumor specific CTLs of healthy individuals as compared with cancer patients [7] , we believe that this could reflect a difference in the interaction kinetics of the T-cell receptor (TCR) [27] . Considering that aged cancer patients present with an involuted thymus and thus have a reduced capacity to flood the periphery with large numbers of naive T cells, it is highly probable that with respect to cancer patients, antigenic encounters in the periphery could modulate the type and size of the T‑cell pool, allowing and/or limiting the window of effective signal transduction, giving rise to the dynamic propagation of clones with a low TCR avidity [28,29] and poor tumor destruction capacity [30] . Notwithstanding the aforementioned effects of replicative senescence, immunosenescence of tumor-specific T cells cannot be underestimated, since it is a complex process that leads to progressive deterioration of immune system components [31] . Immunosenescence is characterized by a progressive decline in thymic functions during adulthood that results in accumulation of regulatory T cells, disruption of the T‑cell population balance due to a decline of naive T‑cell numbers, a shift in the ratio of naive to memory T cells in the periphery to maintain peripheral T-cell homeostasis, reduction in T‑cell repertoire diversity in both CD4 + and CD8 + T cells, and accumulation of memory T cells specific for persisting pathogens, mainly cytomegalovirus (memory inflation) [32–35] . T-cell immunity to persistent antigens (self or foreign) initially leads to expansion of clones with heterogeneous TCR specificities. The persistent chronic antigenic stimulation, however, causes clonal exhaustion resulting in the accumulation of oligoclonal Expert Rev. Vaccines 9(12), (2010)
Determinants of cancer immunotherapy success
dysfunctional cells followed by repertoire shrinkage due to clonal deletion; however, this maintains the actual number of dysfunctional cells [36] . Therefore, attempts by the immune system to sustain responses against persistent antigens leads to the accumulation of these ‘aged’ and inefficient cells, which reduces the diversity of the T-cell repertoire for other antigens, eventually resulting in a loss of TCR diversity against both newly encountered and persistent antigens [9] . Despite efforts by the immune system to maintain homeostasis, the forces driving this phenomenon inevitably lead to a profound and consistent deterioration of function characterized by immunological incompetence [37] . Even though the aforementioned has been convincingly recognized to occur against persistent viral infections [38] , emerging evidence indicates that it can equally occur in cancer. In a study attempting to measure cytokeratin-18-specific peripheral CD8 + T cells in renal cancer, a striking expansion of these T cells was observed in patients (up to 9% of the CD8 + repertoire) and to a lesser extent in healthy donors (not exceeding 0.6%). Despite having a terminally differentiated effector cell phenotype, these CD8 + T cells were unable to produce IFN-g and display cytotoxic activity upon ex vivo peptide-specific stimulation [39] . Our recent findings of functionally impaired tumor-specific CTLs identified in lung cancer patients as opposed to those recognized References 1
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in age-matched individuals [7] , support the notion that if the efficacy of cancer immunotherapy is to be improved, then one must overcome the dysfunctional ‘senescent T cells’ of cancer patients. In conclusion, it appears that recent advancements in our understanding of the interplay of the anti-tumor CD8 + T cell response can determine the fate of cancer immunotherapy. To this end, one must bear in mind that, owing to immunosenescence, the aged cancer patient demonstrates a reduced resevoir and function of the T cells needed for effective anti-tumor immunity. Hence, if we are to expect immunotherapeutic protocols, such as vaccination, to offer an improved alternative for cancer treatment, we must consider approaching this issue from a ‘younger’ perspective, whereby in an adoptive transfer setting, cancer immunotherapy can be dramatically improved by utilizing ‘young’ T cells derived either from cord blood or from the peripheral blood of young subjects [40] . Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
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