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Protection from tumor recurrence following adoptive immunotherapy varies with host conditioning regimen despite initial regression of autochthonous murine brain tumors.

ABSTRACT: Adoptive T cell transfer (ACT) has achieved clinical success in treating established cancer, particularly in combination with lymphodepleting regimens. Our group previously demonstrated that ACT following whole-body irradiation (WBI) promotes high-level T cell accumulation, regression of established brain tumors, and long-term protection from tumor recurrence in a mouse model of SV40 T antigen-induced choroid plexus tumors. Here we asked whether an approach that can promote strong donor T-cell responses in the absence of WBI might also produce this dramatic and durable tumor elimination following ACT. Agonist anti-CD40 antibody can enhance antigen-specific CD8(+) T-cell responses and has shown clinical efficacy as a monotherapy in the setting of cancer. We show that anti-CD40 conditioning promotes rapid accumulation of tumor-specific donor CD8(+) T cells in the brain and regression of autochthonous T antigen-induced choroid plexus tumors, similar to WBI. Despite a significant increase in the lifespan, tumors eventually recurred in anti-CD40-conditioned mice coincident with loss of T-cell persistence from both the brain and lymphoid organs. Depletion of CD8(+) T cells from the peripheral lymphoid organs of WBI-conditioned recipients failed to promote tumor recurrence, but donor cells persisted in the brains long-term in CD8-depleted mice. These results demonstrate that anti-CD40 conditioning effectively enhances ACT-mediated acute elimination of autochthonous tumors, but suggest that mechanisms associated with WBI conditioning, such as the induction of long-lived T cells, may be critical for protection from tumor recurrence.

SUBMITTER: Cozza EM

PROVIDER: S-EPMC4344424 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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Protection from tumor recurrence following adoptive immunotherapy varies with host conditioning regimen despite initial regression of autochthonous murine brain tumors.

Cozza Eugene M EM Cooper Timothy K TK Budgeon Lynn R LR Christensen Neil D ND Schell Todd D TD

Cancer immunology, immunotherapy : CII 20141119 3

Adoptive T cell transfer (ACT) has achieved clinical success in treating established cancer, particularly in combination with lymphodepleting regimens. Our group previously demonstrated that ACT following whole-body irradiation (WBI) promotes high-level T cell accumulation, regression of established brain tumors, and long-term protection from tumor recurrence in a mouse model of SV40 T antigen-induced choroid plexus tumors. Here we asked whether an approach that can promote strong donor T-cell r ...[more]

PMID: 25408469

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Project description:Eyeblink conditioning is the most popular paradigm for studying classical conditioning in humans. But the fact that eyelids are under voluntary control means it is ultimately impossible to ascertain whether a blink response is 'conditioned' or a timed 'voluntary' blink response. In contrast, the pupillary response is an autonomic response, not under voluntary control. By conditioning the pupillary response, one might avoid potential volition-related confounds. Several attempts have been made to condition the pupillary constriction and dilation responses, with the earliest published attempts dating back to the beginning of the 20th century. While a few early studies reported successful conditioning of pupillary constriction, later studies have failed to replicate this. The apparatus for recording pupil size, the type of stimuli used and the interval between the stimuli has varied in previous attempts-which may explain the inconsistent results. Moreover, measuring the pupil size used to be cumbersome compared with today when an eyetracker can continuously measure pupil size non-invasively. Here we used an eyetracker to test whether it is possible to condition the autonomic pupillary constriction response by pairing a tone (CS) and a light (US) with a 1s CS-US interval. Unlike in previous studies, our subjects went through multiple training sessions to ensure that any potential lack of conditioning would not be due to too little training. A total of 10 participants went through 2-12 conditioning sessions, each lasting approximately 20 min. One training session consisted of 75 paired, tone + light, trials and 25 randomly interspersed CS alone trials. The eyetracker (Tobii Pro Nano), continuously measured participants' pupil size. To test statistically whether conditioning of the pupillary response occurred we compared the pupil size after the tone on the first session and the last session. The results showed a complete lack of evidence of conditioning. Though the pupil size varied slightly between participants, the size did not change as a result of the training-irrespective of the number of training sessions. The data replicate previous findings that pupillary constriction does not show conditioning. We conclude that it is not possible to condition pupillary constriction-at least not by pairing a tone and a light. One hypothesis is that when pupillary conditioning has been observed in previous studies, it has been mediated by conditioning of an emotional response.

Dataset Information

Protection from tumor recurrence following adoptive immunotherapy varies with host conditioning regimen despite initial regression of autochthonous murine brain tumors.

Publications

Protection from tumor recurrence following adoptive immunotherapy varies with host conditioning regimen despite initial regression of autochthonous murine brain tumors.

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