IL‐7 is superior to IL‐2 for ex vivo expansion of tumour‐specific CD4⁺ T cells

Abstract

It is well established that tumours hinder both natural and vaccine-induced tumourspecific CD4 1 T-cell responses. Adoptive T-cell therapy has the potential to circumvent functional tolerance and enhance anti-tumour protective responses. While protocols suitable for the expansion of cytotoxic CD8 1 T cells are currently available, data on tumour-specific CD4 1 T cells remain scarce. We report here that CD4 1 T cells sensitized to tumour-associated Ag in vivo, proliferate in vitro in response to IL-7 without the need for exogenous Ag stimulation and accumulate several folds while preserving a memory-like phenotype. Both cell proliferation and survival accounts for the outgrowth of tumoursensitized T cells among other memory and naive lymphocytes following exposure to IL-7. Also IL-2, previously used to expand anti-tumour CTL, promotes tumour-specific CD4 1 T-cell accumulation. However, IL-7 is superior to IL-2 at preserving lymphocyte viability, in vitro and in vivo, maintaining those properties, that are required by helper CD4 1 T cells to confer therapeutic efficacy upon transplantation in tumour-bearing hosts. Together our data support a unique role for IL-7 in retrieving memory-like CD4 1 T cells suitable for adoptive T-cell therapy.Key words: Adoptive T-cell therapy . Cytokines . T helper cells . Tumour immunology Supporting Information available online IntroductionAdoptive cell therapy (ACT) with tumour-specific CD8 1 T lymphocytes has become one of the most promising approaches in cancer therapy. Rosenberg et al. first demonstrated the possibility to expand tumour-specific cytotoxic CD8 1 lymphocytes (CTL) from tumour lesions in high doses of IL-2 [1]. These authors later showed that the state of lymphocyte differentiation, induced in the presence of common g-chain receptor cytokines, is critical for therapeutic efficacy [2,3]. In spite of the recognized importance of Ag-specific CD4 1 T cells in both adaptive and innate immune responses, their identification remains elusive, and their in vitro amplification is hindered by the absence of reliable protocols able to support cell proliferation in the absence of terminal differentiation. While, Ag tumours elicit natural tumour-specific CD4 1 T-cell responses [4][5][6][7][8][9][10], functional tolerance is eventually observed through the induction of T-cell anergy [11,12], T-cell depletion [13] or the limitation of the memory repertoire [10,14,15]. This is possibly due to Ag persistence, and continual TCR signaling, as in the case of chronic 470viral infections [16][17][18]. In addition, regulatory CD4 1 T cells have been frequently found in the case of tumours, often among the tumour-infiltrating lymphocytes, thereby persuading the general interest towards CD8 1 CTL. Thus, CD4 1 T cells have not been widely exploited in ACT as well as the properties (i.e. homing potential, functionality, and survival) that CD4 1 T cells might require for successful applications in ACT are much less known than in the case for CD8 1 CTL.A large, still not definitive, amount of ...

Reduced Functional Avidity Promotes Central and Effector Memory CD4 T Cell Responses to Tumor-Associated Antigens

“…2D). It has been shown previously that transfer of comparable CD4 T cells from tumor-bearing animals was protective against tumor challenge, indicating that the tumor stimulates multiple specificities in addition to the 16.2b epitope (28). Subdivision of total CD44 hi T cells into CD62L hi (TCM) or CD62L lo (TE) showed that WT and LckON mice accumulated similar numbers of both when compared at day 12 after tumor development.…”

“…In the TS/A-LACK adenocarcinoma model, the tumor cells are not direct targets for CD4-mediated killing, because they lack MHC class II expression and their parent line TS/A relies on CD8 + T cells to be rejected (39). However, treatment of tumor-bearing mice with anti-CD4 Ab was shown to result in increased tumor bulk (14), whereas adoptive transfer of tumor-specific CD4 cells conferred partial protection (28), indicating that CD4 helper cells were involved in restricting tumor growth. The 16.2b rearranged Vb4 TCR transgene came originally from a CD4 + cell and may skew the repertoire of CD8 cells that develop in these animals.…”

Antigen-Experienced CD4+ T Cells Limit Naïve T-Cell Priming in Response to Therapeutic VaccinationIn vivo

“…Thus, alternative vaccination strategies able to overcome limitations imposed by Ag-experienced T cells, preexisting to the vaccination, will have to be considered for improving current immunotherapeutic protocols. As an alternative, the ex vivo expansion of tumor-reactive CD4 + T cells could be attempted (18), as adoptive cell therapy might represent a more potent therapeutic option.…”

“…Indeed, vaccination with a class IIrestricted peptide was sufficient to induce protective antitumor immunity in prophylactic settings (16,17), and CD4-based adoptive cell therapy conferred resistance to tumor development (18). However, although CD4 + T cells contributed to the control of tumor growth, they were insufficient for rejection (19), and therapeutic vaccination was largely ineffective (16,17).…”

Adoptive therapy with CAR redirected T cells for hematological malignancies

“…IL-2 can improve the proliferation of T cells (Caserta et al, 2010), and CAR-T cells able to secrete IL-2 and IL-15 were demonstrated to have better tumor-cytotoxicity in pre-clinical experiments (Hoyos et al, 2010;Pegram et al, 2012). IL-2 facilitated tumor-specific T cells to generate IFN- (Overwijk et al, 2003), and IFN- was highly related to CAR-T tumor-cytotoxicity.…”